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Review

Is Autophagy Always a Barrier to Cisplatin Therapy?

1
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
2
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Massey Cancer Center, 401 College St., Richmond, VA 23298, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2022, 12(3), 463; https://doi.org/10.3390/biom12030463
Received: 17 February 2022 / Revised: 10 March 2022 / Accepted: 12 March 2022 / Published: 17 March 2022
(This article belongs to the Special Issue Cisplatin in Diseases: Molecular Mechanisms of Action)

Abstract

:
Cisplatin has long been a first-line chemotherapeutic agent in the treatment of cancer, largely for solid tumors. During the course of the past two decades, autophagy has been identified in response to cancer treatments and almost uniformly detected in studies involving cisplatin. There has been increasing recognition of autophagy as a critical factor affecting tumor cell death and tumor chemoresistance. In this review and commentary, we introduce four mechanisms of resistance to cisplatin followed by a discussion of the factors that affect the role of autophagy in cisplatin-sensitive and resistant cells and explore the two-sided outcomes that occur when autophagy inhibitors are combined with cisplatin. Our goal is to analyze the potential for the combinatorial use of cisplatin and autophagy inhibitors in the clinic.

1. Introduction

Cisplatin (cis-diamminedichloroplatinum (II)) was first approved for clinical use by the FDA in 1978 and has continued to be used as a first-line chemotherapeutic agent for the treatment of approximately 50% of solid tumors, including lung, head and neck, breast, testicular, ovarian, prostate, and bladder cancers [1,2]. Cisplatin was initially synthesized by Michel Peyrone in 1845 and therefore was initially called Peyrone’s salt. In testing the effects of platinum compounds on E. coli proliferation, Rosenberg and his group found that cisplatin also has inhibitory effects on sarcoma 180 and L1210 leukemia cells [3,4]. Prior to this time, chemotherapeutic drugs in the clinic were all natural or synthetic organic compounds, and cisplatin became the first antitumor candidate containing heavy metal elements. After approximately 15 years of preclinical experimentation, through 1975, clinical trials led by the J.M. Hill laboratory confirmed the antiproliferative activity of cisplatin against multiple solid tumors [5]. Although cisplatin has a wide range of antitumor activity, its side effects continue to limit its therapeutic use and efficacy. In the clinic, patients treated with cisplatin often experience symptoms of renal tubular necrosis (nephrotoxicity), hearing loss or cochlear damage (ototoxicity), and peripheral sensory neuropathy (neurotoxicity) [6]. These side effects appear more frequently with increasing doses of the drug. In addition to side effects, patients with solid tumors will frequently develop resistance to cisplatin, forcing physicians to consider other treatment options. As cisplatin resistance is often associated with cross-resistance to other commonly used cytotoxic chemotherapeutic drugs, such as doxorubicin and etoposide, this results in a reduction in treatment options [7]. There are many factors leading to cisplatin resistance, including alterations in DNA metabolism, epigenetic and transcriptional modifications, activation of drug efflux systems, and subcellular drug localization and translocation [8].
The mechanisms mediating the antitumor actions of cisplatin have been studied for decades, with DNA being the primary drug target. Once inside the cell, cisplatin undergoes aquation to form [Pt(NH3)2Cl(OH2)]+ and reacts with DNA to form monoadducts, interstrand, intrastrand or DNA–protein cross-links, affecting the DNA double helix structure and nucleosomes of cancer cells [9,10]. This leads to replication and transcriptional repression, and DNA double-strand breaks (DSBs), which then initiate DNA repair. Once DNA repair fails or is overwhelmed by excessive DNA damage, cell death is triggered [11]. An increased capacity to repair DNA is considered as the most significant feature of platinum-resistant cells [12,13].
The central downstream event following cisplatin interaction with cellular DNA is apoptosis [14,15,16]. The intrinsic pathway of cisplatin-induced apoptosis involves the promotion of oxidative stress, whereby cisplatin-treated cells accumulate excessive reactive oxygen species (ROS) (hydroxyl radicals and superoxide). Abnormally accumulated ROS damages mitochondrial respiratory function, leading to mitochondrial dysfunction [17]. ROS, influencing the pro-apoptotic protein Bax, also cause damage to mitochondrial DNA and a reduction in mitochondrial membrane potential, which promotes mitochondrial destruction. Cytochrome c and caspase 9 are then released by damaged mitochondria and evoke a cascade of caspase cleavage reactions [18].
The extrinsic pathway of cisplatin-induced apoptosis is mediated via a type-II membrane protein that activates the Fas receptor in conjunction with the Fas ligand, thereby promoting the formation of the apoptosome complex by the Fas-associated death domain and pro-caspase 8. This apoptosome complex activates caspase 3, caspase 6, and caspase 7, ultimately leading to apoptosis [19]. In addition, cisplatin generally arrests cells in the G1/S or G2 phase of the cell cycle, providing time for repair of damaged DNA prior to DNA synthesis. When cells fail to repair DNA damage at the cell cycle checkpoints, they are forced to re-enter the cycle prematurely, progressing to apoptosis [20,21]. As a “gatekeeper”, the activation of p53 also contributes to cisplatin-induced tumor cell apoptosis [22]. In addition, the p21, MDM2, GADD45 [23], MAPK pathway [24], and PI3K/Akt pathways [25], which are related to p53 and cell cycle regulation, have all been shown to be involved in cisplatin-induced apoptosis.
Macroautophagy (which we will refer to as autophagy) is a critical process in eukaryotic cells whereby superfluous organelles, misfolded proteins, and other cellular debris are cleared, restoring a state of cellular equilibrium [26]. This process is an evolutionarily conserved process whereby cellular debris or toxic cellular components are engulfed by the autophagosome, a double-layered membrane structure, and transported to acidic lysosomes, where they undergo degradation and recycling [27]. Autophagy occurs in cells under nutrient-poor conditions, responding to the decline in external energy sources. Therefore, autophagy is generally considered to reflect a survival-promoting function. However, if autophagy is continuously or overly activated, cell death will be triggered. Upon cisplatin treatment, autophagy induction has been detected in both cisplatin-sensitive and cisplatin-resistant cancer cells. In fact, the basal level of autophagy was significantly elevated in cisplatin-resistant cells [28,29,30,31].
Defective apoptosis is one cause of cisplatin resistance, which confers a survival advantage to tumor cells. This defect facilitates the generation of cellular stress-mediated autophagy, which precedes or effectively blocks the apoptotic cascade. A large number of studies have shown that when cisplatin-induced autophagy is inhibited in cancer cells, the manner of cell death switches to apoptosis [28]. Therefore, taken together, cisplatin-induced autophagy is often considered one of the primary factors thwarting its chemotherapeutic effects. However, the role of autophagy is often far more complex than has been appreciated.
In addition to autophagy and apoptosis, the tumor cell response following cisplatin treatment can include cellular senescence, as in some cases, persistent DNA damage leads to long-term growth arrest [32]. Although senescence was previously considered an irreversible response after chemotherapy, recent studies from a number of laboratories, including our own, have shown that tumor cells have the capacity to escape from this therapy-induced senescence [33]. In this review, we focus on the influence of cisplatin-induced autophagy on the response of solid tumors to this therapy.

2. Cisplatin-Induced Autophagy

2.1. Cisplatin Resistance

Clinical resistance is defined as the failure of tumor cells to undergo apoptosis at clinically relevant doses or at clinically achievable plasma drug concentrations. The mechanisms conferring cisplatin resistance are numerous and include the following (Figure 1):
(a) Decrease in DNA adduct generation: This can result from a number of factors including decreased drug uptake, increased drug efflux, interference with intracellular trafficking and subcellular distribution, increased levels of glutathione (GSH) and the cysteine-rich metallothionein in the cytoplasm in response to cisplatin activation [34], and increased DNA adduct repair by non-homologous recombination. Among these, the most attention in recent years has been paid to the intracellular trafficking and subcellular distribution of cisplatin. Researchers have detected increased cisplatin accumulation in cellular compartments such as Golgi, lysosomes, melanosomes, and exosomes [35], but how cisplatin accumulates in these organelles has not been fully elucidated. Among these, the lysosomal transport of cisplatin [36] was demonstrated to be associated with reduced cytotoxicity (and even resistance) to this drug [37,38,39]. According to this view, lysosomes are regarded as a detoxifying organelle that sequesters both metals and metal-containing drugs and removes them via the exosomal pathway. By doing so, lysosomes tend to reduce the cellular accumulation of cisplatin via exocytosis or its reduced uptake (or both) and transfer the drug to other subcellular targets, thus reducing its cytotoxicity [38,40].
(b) DNA damage recognition defects and increased DNA damage tolerance: Damage recognition proteins such as the mismatch repair (MMR) complex generally promote cisplatin-mediated apoptosis after ineffective repair of DNA adducts. However, if the integrity of the MMR complex is lost, the response to cisplatin is significantly reduced [41].
(c) Inhibition of apoptosis: As mentioned in the introduction, cisplatin is a potent inducer of apoptosis. A loss of apoptotic signals elevates the threshold of DNA damage for inducing cell death, which is also one of the ways that cells improve DNA damage tolerance [42]. p53 is one of the key factors regulating cisplatin-induced apoptosis, as p53 not only participates in apoptosis but also in the activation of checkpoints following platinum–DNA complexation [43]. Thus, when p53 is mutated, the three-dimensional structure of p53 is altered and can no longer bind to DNA in a sequence-specific manner to transactivate proteins, including cyclin-dependent kinase (CDK) inhibitors, p21Waf1/Cip1, p53 feedback inhibitor murine double minute 2 (MDM2) [44], the growth arrest and DNA damage-inducible Gadd45a gene, and the BCL-2 family, where apoptosis resistance occurs, thereby reducing the susceptibility of tumor cells to cell death [45,46,47].
(d) Induction of cytoprotective autophagy: In response to chemotherapy, autophagy can exhibit several functional forms, including a cytoprotective form that plays a pro-survival role, a cytotoxic form that promotes tumor cell death, and a nonprotective form, which does not seem to directly affect cell proliferation or apoptosis [48]. When proposing that autophagy may suppress cisplatin sensitivity or lead to drug resistance, it is necessary to distinguish the function of autophagy. This is because although cisplatin often induces the cytoprotective form of autophagy, whereupon autophagy inhibition enhances cisplatin efficacy, our research group as well as other laboratories have found that cisplatin can also induce non-protective autophagy and cytotoxic autophagy [49,50]. Furthermore, we and others have reported on the existence of an “autophagic switch” due to manipulation of the status of specific genes [51,52,53,54]. For example, after cisplatin treatment, non-protective autophagy in p53 H460 cells can be “switched” to cytoprotective autophagy in CRISPR/cas9 p53 H460 cells [50].

2.2. Factors That Affect the Role of Autophagy in Cisplatin-Sensitive Cells

ATM-CHK2 and ATR-CHK1 pathways: The DNA damage chemotherapeutic drug response has largely been defined in the context of the ataxia telangiectasia mutated (ATM)-CHK2 and RAD3-related (ATR)-CHK1 pathways. Cell cycle-related proteins downstream of ATM and ATR such as p53, p21, MAPK, AMPK, and PTEN are inextricably linked to the proliferation of tumor cells. Reinhardt et al. found that activation of the ATM/ATR-p38 MAPK-MK2 pathway in p53-deficient cells is required for resistance to DNA-damaging chemotherapeutic agents such as cisplatin [55]. However, we as well as other researchers have found that the deletion of p53, AMPK, or PTEN does not affect the induction of autophagy by cisplatin [50,56], suggesting that there must be other key factors that regulate autophagy in cisplatin-treated cells. A further study by Gomes et al. found that in their 3D-rBM cell model, although the p53 status did not affect cisplatin sensitivity, the inhibition of ATR enhanced cisplatin-induced cell death [57]. A recent study by Chen et al. showed that the ATM-CHK2 axis is associated with cisplatin-induced autophagy via modulation of FOXK proteins, members of the forkhead transcription family. While these can act as transcriptional repressors of autophagy, DNA damage promotes phosphorylation of the FOXK proteins via CHK2, resulting in their being trapped in the cytoplasm and thereby promoting protective autophagy. Furthermore, a cancer-derived FOXK mutation also induced FOXK hyperphosphorylation, exacerbating autophagy and drug resistance. Consequently, the combination of chloroquine (CQ) with cisplatin has a strong growth-inhibitory effect in tumor cells expressing these cancer-derived FOXK mutants [56].
AMBRA1: Activating molecule in Beclin1-regulated autophagy (AMBRA1) is an important factor in regulating autophagy and cell proliferation. AMBRA1 promotes autophagy by activating ULK1 and the BECN1-PIK3C3/VPS34 complex [58,59]. Using a genetic knockdown approach, AMBRA1 was found to mediate cisplatin-induced autophagy and chemosensitivity in prostate cancer [60] and cervical cancer [61]. A recent study further clarified the mechanism of AMBRA1 as being related to the tumor cell response to cisplatin. Antonioli et al. found that human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) had higher autophagy levels as well as higher AMBRA1 levels compared with HPV-positive OPSCC, while knockdown of AMBRA1 decreased cisplatin-induced cytoprotective autophagy in HPV-negative OPSCC [62]. These studies suggest that AMBRA1 may serve as a potential target in combination with cisplatin when autophagy plays a protective role.
Galectin-1: Galectin-1 is a member of a family of galectins with an affinity for β-galactosides, that is involved in cell adhesion, cell cycle progression, and apoptosis [63]. It is detected in the periphery of tumor cells and is involved in various stages of tumor cell proliferation, in addition to its involvement in the inflammatory response [64]. However, an increasing number of studies have indicated the inconsistent biological functions of galectin-1 in intracellular and extracellular compartments on tumor cells (i.e., extracellular galectin-1 induces anti-proliferative effects via the Ras/MAPK pathway, whereas intracellular galectin-1 exhibits the ability to promote tumor transformation) [65]. Due to the diversity of its biological functions, researchers have been attracted to exploring its effect on the antitumor actions of platinum-based chemotherapy drugs. Chung et al. found that galectin-1 was overexpressed in lung cancer cells and the tissues of lung cancer patients and was associated with Ras, p38 MAPK, ERK, and NF-κB. They also found that knockdown of galectin-1 increased the sensitivity of A549 cells to cisplatin [66]. It has also been reported that galectin-1 knockdown promotes cisplatin sensitivity in other tumor cells, such as bulky squamous cervical cancer [67] and epithelial ovarian cancer [68]. Gao et al. asserted that the inhibitory effect of galectin-1 on cisplatin sensitivity may be related to its induction of autophagy [30]. Further analysis of the relationship between galectin-1 and cisplatin-induced autophagy determined that inhibition of autophagy abolished the resistance to cisplatin conferred by galectin-1 in hepatoma cells [69]. Interestingly, however, we noted that in their studies, silencing of ATG5 or pharmacological inhibition of autophagy by Bafilomycin A pretreatment did not enhance cisplatin-induced cell death in Huh7 cells. Therefore, we suggest that cisplatin likely induced non-protective autophagy in Huh7 cells, while the exogenous addition of galectin-1 not only accelerated hepatocellular carcinoma cell death but also promoted the cisplatin-induced autophagy switch from non-protective autophagy to protective autophagy.
ARHI: Bast et al. found that the oncogene ARHI (DIRAS3), a gene downregulated in 60% of cervical cancers [70], is involved in cell proliferation [71,72], migration [73], autophagy, and tumor dormancy [74,75] regulation. Their study suggests that ARHI may also have a regulatory role in the cisplatin-induced autophagic switch. These investigators reported that in a nude mouse xenograft model of ARHI-re-expressing SKOV3 cells, treatment with CQ significantly delayed the regrowth of the dormant tumor cells after withdrawal of ARHI [75]. Complementary findings were reported by Li et al., who observed that overexpression of ARHI in TOV12D and ES2 ovarian cancer cells significantly delayed xenograft growth by inhibiting AKT activity and decreasing Bcl-2 expression, inducing apoptosis and autophagic cell death [76]. Bast et al. subsequently found that autophagy inhibition using CQ or shATG5 had no significant effect on cisplatin-induced colony formation or cell survival in ARHI-negative SKOV-3, Hey, and OVCAR4 cells, suggesting that non-protective autophagy was induced [77]. These results again allude to our previous view that cisplatin-induced autophagy is not always promoting or inhibitory to tumor growth and that there is also “nonsense” autophagy (i.e., a non-protective form of autophagy whose inhibition does not alter sensitivity to the autophagy-promoting stimulus). In contrast, ARHI re-expression enhanced the sensitivity to cisplatin both in vitro and in vivo, and the combined treatment with CQ attenuated the enhanced effect of ARHI on cisplatin chemosensitivity, implying that here, autophagy played a role in promoting cell death in ARHI re-expressed cells (e.g., cytotoxic autophagy) [77]. These results suggest that high expression of ARHI can have a positive role in promoting cisplatin activity against cervical cancer. On the other hand, re-expression of ARHI induced the switch to cytotoxic autophagy from non-protective autophagy, which should suggest caution in that that the use of CQ in combination with cisplatin therapy in patients with high ARHI expression has the potential to generate an undesirable outcome.
ECRG4: Esophageal carcinoma-related gene 4 (ECRG4) is a novel candidate tumor suppressor gene that has frequently been found to be inactivated by promoter hypermethylation in different cancer types, including esophageal cancer, prostate cancer, gastric cancer, colorectal carcinoma, and glioma [78,79,80]. ECRG4 is also identified as a paracrine factor-activated microglia, which has effects on the chemotaxis of monocytes and potential as a target for anti-tumor therapy [81]. You et al. showed that ECRG4 overexpression not only promotes cisplatin chemosensitivity but also plays a role in the cisplatin-induced autophagic switch. They found that 3-methyladenine (3-MA) had no effect on the survival of cisplatin-induced nasopharyngeal carcinoma CNE1 cells, but it decreased the chemosensitivity of cisplatin in ECRG4-overexpressing CNE1 cells [82]. This suggests that ECRG4 overexpression leads to the cisplatin-induced autophagic switch from nonprotective autophagy to cytotoxic autophagy. However, studies on the relationship between this gene and autophagy regulation are relatively limited.
PFKFB3: Upregulation of glycolytic metabolic pathways is associated with cancer progression [83]. The activity of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme (PFKFB3) represents one of the rate-limiting steps in mediating the conversion of fructose-6-phosphate to fructose 2,6-bisphosphate (F-2,6-BP) in the glucose metabolic pathway. PFKFB3 is highly expressed in a variety of tumors [84], such as head and neck squamous cell carcinoma [85], hepatocellular carcinoma [86], breast and colon cancer [87], gastric cancer [88], and ovarian cancer [89]. PFKFB3 inhibition was found to induce B16-F10 tumor vessel normalization, impaired metastasis, and improved cisplatin chemosensitivity [90]. Similar results were reported by Li, who found that PKF15, an inhibitor of PFKFB3, sensitized tumors to cisplatin treatment in a xenograft model [91]. Following this, a recent study showed that PFK158, another PFKFB3 inhibitor, also promotes cisplatin chemosensitivity in endometrial cancer through the induction of cytotoxic autophagy via inhibition of the PI3K/Akt/mTOR pathway [92]. These positive outcomes support the potential combination of inhibitors of PFKFB3 with cisplatin.

2.3. Factors That Affect the Role of Autophagy in Cisplatin-Resistant Cells

p53: As mentioned above, the status of the tumor suppressor p53, which is generally regarded as a key cellular defense mechanism against cancer, can influence cisplatin sensitivity. Tung et al. demonstrated that wild-type p53 in non-small cell lung cancer (NSCLC) cells inhibits the Nrf2 promoter’s activity to promote cisplatin-induced apoptosis. In contrast, mutant p53 causes apoptosis resistance due to its inability to inhibit the activity of Nrf2, followed by the induction of the anti-apoptotic protein Bcl-2 and increased expression of Bcl-XL [93]. These studies support the necessity for p53 in the process of cisplatin-induced apoptosis in NSCLC cells. Although the promoting effect of wild-type p53 on the efficacy of cisplatin is easy to understand, clinical trials 20 years ago found that this effect and the type of tumor are interrelated, and the results have not always been consistent. Clinical trials have found that for the treatment of cervical cancer, p53 wild-type patients do not respond optimally to cisplatin [94]. More interestingly, for testicular cancer, a tumor that is highly sensitive to cisplatin, almost all of the few refractory patients have been found to harbor wild-type p53, which is not consistent with the commonly accepted view that tumors with p53 mutations are more therapy-resistant [95]. In addition, the Kroemer laboratory found that the regulation of autophagy was associated with the subcellular localization of p53. In short, p53 in the cytoplasm inhibited autophagy, whereas p53 in the nucleus, in contrast, induced autophagy [96]. It is tempting to speculate that the influence of p53 on cisplatin-induced autophagy is also inconsistent. A recent study showed that re-expression of p53 in p53-null SKOV3 cells increased cisplatin-induced autophagy and apoptosis in vivo and in vitro, while the induction of p53 in ERK-active Ras-expressing cells did not further induce autophagy but reversed the cisplatin resistance to sensitivity, indicating that the wild-type p53 status determines the role of autophagy in ovarian cancer chemoresistance [97]. This result is consistent with a study from Rosenfeldt et al., who demonstrated that treatment with the autophagy inhibitor hydroxychloroquine (HCQ) significantly accelerated tumor formation in autophagy-competent mice with oncogenic KRAS but lacking p53 [98]. These results all imply that the status of p53 influences the occurrence and the nature of autophagy. However, the outcomes in cisplatin-sensitive cells are complicated. Studies from the Gewirtz laboratory demonstrated that the status of p53 has no effect on the extent of autophagy but instead influence the nature of the autophagy. H460 p53 wild-type cells exhibited nonprotective autophagy in response to cisplatin treatment, whereas CRSPR/Cas 9 knockout of p53 H460 cells demonstrated cytoprotective autophagy [50]. Similar to the outcomes of this work, Tripathi et al. found that cisplatin induced cytoprotective autophagy in p53 knockdown embryonal carcinoma cells [99]. Maycotte et al., however, found non-protective autophagy in p53-null mouse breast cancer cells (67NR and 4T1 cells) after exposure to cisplatin [100]. Unlike these findings, Gomes et al. found that, whether the breast cancer cells or lung cancer cells responded to cisplatin in traditional two-dimensional (2D) or in 3D reconstitution-based membrane cell culture models, cisplatin-induced autophagy appeared to be independent of the p53 status [57]. These results indicate that p53 clearly may play a key role in cisplatin-induced autophagy, and this is particularly important in cisplatin-resistant cells.
RASSF1A: RAS association domain containing family 1A (RASSF1A), a tumor suppressor gene frequently inactivated in human cancers, is phosphorylated on ser131 by ATM following DNA damage, leading to an apoptotic response [101]. Koul et al. showed that promoter hypomethylation of the RASSF1A gene plays a role in cisplatin resistance in male germ cell tumors [102]. Similar results were found in a clinical trial after paclitaxel-carboplatin or gemcitabine-cisplatin treatment, where methylation of RASSF1A negatively impacted the prognosis of early-stage NSCLC [103]. Levesley et al. found that cisplatin induced more extensive apoptosis in RASSF1A-complete pediatric medulloblastoma UW228-3 cells, further identifying the RASSF1A tumor suppressor as a promoter of apoptotic signaling pathways [104]. In addition, cisplatin decreased the ability of ATM to phosphorylate RASSF1A-p.133Ser and to affect p53 activation [101]. Because RASSF1A, similar to p53, is a tumor suppressor gene that is involved in cisplatin-induced apoptosis, the relationship between RASSF1A and autophagy has attracted the interest of researchers. Surprisingly, unlike p53, a recent study suggests that the activation of RASSF1A may activate the Keap1-Nrf2 pathway by regulating microtubule-associated protein 1s (MAP1S), thus activating cytotoxicity autophagy to enhance the chemosensitivity of cisplatin in cisplatin-resistant NSCLC [105]. However, further investigation is required to determine whether the tumor suppressor role of RASSF1A is related to the activation of cytotoxic autophagy.
APE1: Apurinic/apyrimidinic endonuclease 1 (APE1) can repair DNA damage and regulate select processes related to cell survival, proliferation, and migration through the base excision repair (BER) pathway. Its regulatory role is inextricably linked to nuclear factor-κB (NF-κB) [106], hypoxia inducible factor 1α (HIF-1α) [107], p53 [108], signal transducer and activator of transcription 3 (STAT3) [109], and nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) [110]. Clinical samples and preclinical studies of cisplatin suggest that APE1 is associated with NSCLC invasiveness, a poor prognosis, and cisplatin resistance [111,112,113,114]. Li et al. demonstrated that APE1 was not only overexpressed in cisplatin-resistant A549 cells but also had a correlation with cisplatin-induced autophagy [115]. This conclusion was further refined by Pan et al., whose experiments showed that cisplatin-induced cytoprotective autophagy in KRASG12S-mutant A549 cells and the combined treatment of CQ with APE1 siRNA increased cisplatin sensitivity [116]. The above studies suggest that APE1 overexpression is often detected in NSCLC and is associated with cisplatin-induced cytoprotective autophagy.

2.4. The Non-Coding RNA That Affects the Role of Autophagy in Cisplatin-Treated Cells

Francis Crick’s “central dogma” states that genetic information is transmitted through the DNA–RNA–protein sequence. In this process, however, there are always some genes that are not translated into proteins, which are called non-coding RNAs (ncRNAs). Many ncRNAs have been discovered and shown to be involved in regulating cellular processes and pathways in cancer. Some of these long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs were demonstrated to mediate cisplatin-induced cytoprotective autophagy. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is located on chromosome 11q13 and has been identified to be involved in cancer development and progression [117]. Hu et al. found that CQ enhanced cisplatin-induced apoptosis in vincristine-resistant SGC-7901 cells, indicating that cisplatin-induced resistance in gastric cancer cells is associated with autophagy. They also found that lncRNA MALAT1 enhanced cisplatin-induced cytoprotective autophagy by sequestering mir-23b-3p and increasing the level of ATG12 [118]. lncRNA MALAT1 has also been found to be highly expressed in cisplatin-resistant AGS and HGC-27 gastric cancer cells and promotes autophagy through suppression of the miR-30b/ATG5 and miR-30e/ATG5 axes, thereby reducing cisplatin sensitivity [119,120]. In addition, the regulation of cisplatin-induced autophagy by circRNAs has also been reported. Peng et al. found that circCUL2 regulated cisplatin sensitivity through mir-142-3p/Rock2-mediated autophagy activation in AGS/cisplatin and SGC-7901/cisplatin cell lines [121]. It is interesting to note that miRNA is also reported to be involved in cisplatin-induced protective autophagy, but it is more commonly observed in gastric cancer cells. For example, miR-148a-3p reconstitution in cisplatin-resistant cells inhibits cytoprotective autophagy by suppressing RAB12 expression and mTOR1 activation [122]. MiR-216a-5p overexpression decreased Bcl-2 expression, enhanced Beclin1 expression, and activated cisplatin-induced autophagy [123]. However, more interestingly, for the gastric cancer cell line SGC-7901, the research of Zhu et al. showed that CQ also decreased cisplatin sensitivity and induced cytotoxic autophagy [49]. In contrast to the inconsistent reports in gastric cancer cells, the role of ncRNAs seems to be relatively consistent for cisplatin-induced autophagy in lung cancer cells. For example, LncRNA BLACAT1 [124], miRNA-1 [125], miR-181 [126], miR-223 [127], and miR-425-3p [128], whose overexpression was reported to upregulate cisplatin-induced autophagy, were associated with resistance to cisplatin in lung cancer cells.
There are many other reports relating to the regulation of cisplatin-induced autophagy in tumor cells by different species of ncRNA [129], such as the enhancement of cisplatin-induced autophagy in thyroid cancer cells by overexpression of MicroRNA-125b in vivo and in vitro [130]. Although we will not list all of these studies here, it is important to emphasize that virtually all of these studies are missing the necessary experiments to confirm the role of cisplatin-induced autophagy. Although it has been reported that cisplatin-induced apoptotic cell death was enhanced by the blockade of either siRNA-mediated knockdown of Atg7 genetic expression or a pharmacological inhibitor (3-MA) in NSCLC [131], we and other labs indeed observed that the use of CQ or other autophagy inhibitors did not enhance cisplatin-induced apoptotic cell death (i.e., non-protective autophagy) [50,100] or reduce the cell death rate’s decline (i.e., cytotoxic autophagy) [49]. The current status of the research is that many studies are somewhat handicapped by the preconceived notion that cisplatin-induced autophagy is cytoprotective and related to cisplatin resistance. Therefore, after knockdown or overexpression of ncRNAs, a decreased level of autophagy is observed (usually, only downregulation of LC-I to LC3-II is detected), leading to the possibly incorrect conclusion that the specific ncRNA mediated cisplatin chemoresistance by regulating autophagy.

2.5. Other Genes That Affect the Role of Autophagy in Cisplatin-Treated Tumor Cells

In addition to the more widely reported genes listed above, the expression of many other genes has been shown to affect cisplatin chemosensitivity by regulating autophagy. These include BCAT1 [132], protein disulfide isomerase family 6 (PDIA6) [133], serum-and glucocorticoid-inducible kinase 2 (SGK2) [134], inhibitor of DNA binding 1 (ID1) [135], O-6-methylguanine-DNA methyltransferase (MGMT) [136], PDZ-binding kinase (PBK) [137], IGF2R [138], caveolin-1 (Cav-1) [139], HSP90AA1 [140], O-GlcNAc transferase (OGT) [141], neutrophil gelatinase-associated lipocalin (NGAL) [142], and GFRA1/GFRα1 (GDNF family receptor α1) [143]. However, it is necessary to strongly emphasize that when studying the relationship between specific genes and cisplatin-induced autophagy, it is critical to clarify the function of autophagy in the study model; otherwise, any conclusions that might be drawn would be lacking a rigorous experimental foundation.

3. The Yin and Yang Faces of Autophagy Inhibition in Cisplatin Therapy

Cisplatin treatment promotes autophagy in both cisplatin-sensitive and cisplatin-resistant cells. Consequently, inhibition of autophagy can be considered a strategy for improving cisplatin chemosensitivity [29,30,31]. This is the positive side, which is what we call Yang. However, as discussed in Section 2, the functional activity of cisplatin-induced autophagy is related to different genetic phenotypes and tumor types as well as the microenvironment of the tumor. In addition, preclinical studies have found that pharmacological autophagy inhibitors are not uniformly effective in enhancing the effectiveness of cisplatin and may also exacerbate the side effects of cisplatin toward normal tissue. This is the negative side, which we call Yin. We will next elaborate on the two elements that autophagy inhibition brings to cisplatin treatment in terms of both therapeutic efficacy and side effects.

3.1. A Beneficial Treatment Strategy of Autophagy Inhibition Combined with Cisplatin Is Closely Related to Tumor Types

CQ and HCQ are quinoline derivatives that exhibit a variety of activities and are able to cross cell membranes by passive diffusion. These drugs accumulate and are subsequently protonated in acidic vesicles such as lysosomes. This accumulation leads to a weakened acidic environment, thereby disrupting the endolysosomal system [144]. The fusion of lysosomes and autophagosomes is a critical step for the completion of autophagy, sometimes referred to as autophagic flux. CQ interferes with the fusion process and is therefore considered to be an effective inhibitor of late-stage autophagy [145]. The combination of CQ with cisplatin has been reported to not only increase the chemotherapeutic efficacy of cisplatin-sensitive cancer cells [145] but also to effectively improve the chemosensitivity of cisplatin-resistant cancer cells (Table 1). For example, as listed in Table 1 below, CQ increased cisplatin sensitivity by inhibiting autophagy in cisplatin-resistant A549 (A549/cisplatin) [146], endometrial cancer [147], urothelial carcinoma [148], epithelial ovarian cancer [149], esophageal cancers [29], and neuroblastoma [150]. Apart from the generally recognized autophagy inhibitory effect, recent studies have also reported autophagy-independent activities of CQ against breast cancer [100], as well as increased cisplatin sensitivity to laryngeal tumor cells by promoting repolarizing tumor-associated macrophages from M2 to M1 in vivo and in vitro [151].
The above studies appear to suggest that the combination of CQ and cisplatin is indeed a potential approach to overcoming cisplatin resistance, where this sensitizing effect is largely relevant to specific tumor types. For instance, in patients with cisplatin-resistant oral squamous cell carcinoma, inhibition of autophagy does not seem to be an ideal treatment. A recent study showed that although CQ increased the apoptosis rate of cisplatin-treated SSC-4 cells, it had a very limited effect on the apoptosis of cisplatin-resistant SSC-4 cells (only about a 5–7% increase) [152].
For cells that are inherently sensitive to cisplatin, the outcomes for CQ in combination with cisplatin seem to be more relevant to the tumor types. For example, in cisplatin-sensitive glioblastoma, pediatric medulloblastoma cell lines, atypical teratoma/rhabdomyosarcoma cell lines [153], low ARHI-expressing ovarian cancer SKOV3 cells [77], p53 wild-type lung cancer H460 cells [50] and p53-null mouse breast cancer 67NR and 4T1 cells [100], CQ had no significant effect on the activity of cisplatin (Table 1).
In addition to CQ, Bafilomycin-A1 and PI3K inhibitors (3-MA and wortmannin) are also common inhibitors of autophagy and have been reported to increase the chemosensitivity of cisplatin in different tumor cells in a large number of studies, which have been summarized in many reviews [28]. Nevertheless, there are also exceptions. An example is that the 3-MA showed no effect on the cell proliferation rate in cisplatin-treated nasopharyngeal carcinoma CNE1 cells [82]. More interesting examples are cisplatin-resistant gastric cancer KATO-III cells, for which studies have shown that the resistance is independent of MRP1 and MDR1 and rather linked to Aldoketoreductase1 C1 and C3 (AKR1C1 and AKR1C3). When AKR1C1 and AKR1C3 were inhibited, the combination of 3-MA paradoxically decreased the cell death rate of KATO-III induced by cisplatin [154].
Based on the data presented above using combinations of autophagy inhibitors with cisplatin, although most of the reported cisplatin-resistant cells demonstrated sensitization from the combination treatments, inefficient or even ineffective outcomes were also evident. Moreover, most of the experimental data were generated solely in in vitro cellular models. Furthermore, the paradigm that “autophagy is a drug resistance mechanism” may have occasionally resulted in a less than objective interpretations of the data.
In addition to these more classical autophagy inhibitors, there are some compounds and nanomaterials that have also been found to overcome cisplatin resistance by disrupting autophagy. U0126, a MAPK inhibitor, enhanced cisplatin-induced apoptosis by inhibiting autophagy in cisplatin-resistant ovarian cancer cells [155] and NSCLC cells [156]. Some natural products have also been found to promote the activity of cisplatin by regulating autophagy (Table 2). For example, astragaloside IV (AS-IV) derived from Astragalus membranaceus sensitizes cisplatin-resistant NSCLC cells to cisplatin by inhibiting ER stress and autophagy [157]. However, the role of autophagy induced by natural products in combination with cisplatin is not consistent. For instance, Gardenia jasminoides (GJ), a medicinal herb abundant with flavonoids, in combination with cisplatin paradoxically activated cytotoxic autophagy in glioblastoma multiforme [158]. In addition, the combination of autophagy-inhibiting nanoparticles or materials with cisplatin enhanced the chemosensitivity or reduced the resistance to cisplatin. For instance, a nanoparticle-based co-delivery system ([email protected]) is centered on the efficient co-delivery of Beclin1 siRNA (Beclin1 is an autophagy initiation factor) and cisplatin to enhance the inhibitory effect on cisplatin-resistant A549 cells by inhibiting autophagy in vivo and in vitro [159]. Compared with the poly lactic acid (PLA) + cisplatin nanoparticles (CDDP-PLA NPs), the PLA + cisplatin-CQ nanoparticles (CDDP/CQ-PLA NPs) reduced autophagy and enhanced the ROS and apoptosis of Cal-27 cells [160].
One final issue that we suggest is worthy of additional attention is the “switch” between the roles played by autophagy in different tumors. As mentioned earlier, although in many if not most cases where cisplatin-induced autophagy has been detected the autophagy was functionally cytoprotective, particularly in cisplatin-resistant cells, the non-protective form of autophagy (i.e., where autophagy inhibition failed to influence cisplatin sensitivity) has also been observed, particularly in cisplatin-sensitive cells [50,77,100]. However, interestingly, re-expression of ARHI in SKOV3 cells allowed for CQ to suppress cisplatin sensitivity [77], whereas knockdown of p53 in H460 cells resulted in enhanced cisplatin sensitivity [50], which is what we refer to as the “autophagic switch”. This again argues that studies to improve the efficacy of chemotherapy by altering autophagy function should first distinguish the role of autophagy in specific models. In the absence of such a strategy, experimental conclusions in preclinical models may prove to be flawed, while translation of the work could be compromised.

3.2. Does Autophagy Inhibition Have the Potential to Exacerbate the Toxicity of Cisplatin to Normal Tissue?

The above extensive literature strongly suggests that inhibition of autophagy could, in fact, prove to be an effective strategy for combating cisplatin resistance in the clinic. However, this approach does not fully consider, for example, the troublesome issue of cisplatin toxicity to the kidneys. Cisplatin nephrotoxicity is related to the excretion of cisplatin, which occurs through the kidney tubular epithelial cells. Asymptomatic elevation of serum creatinine levels or even acute tubular injury requiring dialysis therapy occurs with cisplatin chemotherapy in the clinic. Patients who present with this condition often need to have their medication doses reduced to avoid further kidney damage, resulting in under-treatment of the disease [167]. Renal injury is often accompanied by other complications such as water and nitrogenous waste retention and is associated with a poorer patient prognosis [168]. Recent studies have shown that proximal tubule-specific autophagy-deficient mice are more susceptible to kidney injury after cisplatin treatment than wild-type mice [169]. This may be related to autophagy protecting the proximal tubular cells from mitochondrial oxidative stress and protecting the proximal tubular cells from DNA damage. Furthermore, autophagy also protects the proximal tubular cells from ischemic injury [170]. Zhang et al. reported that the mechanism of cisplatin nephrotoxicity may be related to the inhibition of autophagy by the activation of protein kinase C δ [171]. Li et al. found that 3-dehydroxyceanothetric acid 2-methyl ester (3DC2ME) isolated from the roots of jujube (Ziziphus jujuba, Rhamnaceae) protected against cisplatin-induced renal epithelial LLC-PK1 cell injury via autophagy modulation [172]. Retinoic acid, a major derivative of vitamin A, attenuates cisplatin-induced acute kidney injury by activating autophagy [173]. Numerous reports have demonstrated a protective effect of autophagy against cisplatin-induced renal cell injury [174]. Thus, prolonged coadministration of high doses of CQ or other autophagy inhibitors may exacerbate the nephrotoxicity of cisplatin. An example of this outcome can be taken from a study of amniotic fluid stem cells (AFSC) by Minocha et al., who found that AFSC reduced cisplatin-induced renal apoptosis in rats and served to protect against acute kidney injury, but CQ counteracted the renal protective effect of the AFSC [175]. The protective effect of autophagy was also demonstrated in cisplatin-induced damage to the cochlear cells [176]. In addition, the current study also demonstrates the importance of autophagy in enhancing the therapeutic potential of stem cell therapy in attenuating cisplatin-associated liver injury [177]. The two-sided nature of autophagy inhibition during cisplatin treatment suggests the necessity of elucidating the pattern of autophagy in therapy and finding ways to target the delivery of autophagy inhibitors to lesions while mitigating nephrotoxicity as well as other normal tissue injury associated with the administration of cisplatin in cancer therapy.

4. Autophagy in Cisplatin Combination with Immunotherapy

The Beth Levine laboratory reported 20 years ago that beclin 1+/− mice spontaneously develop lymphomas, lung cancer, as well as liver cancer [178,179], implicating autophagy in the protection of normal tissues from transformation. Subsequent studies found that this observation may be related to the role of autophagy in the immune system. Autophagy deficiency disrupts the clearance of malignant cells by dendritic cells and CD8+ T cells. Autophagy also has a facilitative role in tumor antigen cross-presentation and enhances the tumor responsiveness of the immune system [180]. However, autophagy can play an opposite role in the developmental process of established tumors. The deficiency of ATG7, an autophagy-associated gene that is essential for autophagosome production, delayed PTEN-deficient prostate tumor progression [181]. Lévy et al. showed that the loss of ATG7 promotes adaptive immunity, during which CD8+ T cells are necessary to prevent intestinal adenomas in APC+/− mice [182]. This suggests the need for autophagy as a “guardian” in the early stages of tumor formation and as an “accomplice” for tumor survival in the later stages.
During chemotherapy, autophagy also acts as a signal in the process of immune recognition and immunogenic cell death (ICD) [183,184]. Among the several cytotoxic antitumor compounds investigated (cisplatin, carboplatin, etoposide, paclitaxel, and gemcitabine), cisplatin was demonstrated to induce the highest levels of ICD-associated damage-associated molecular patterns (DAMPs) [185]. This study suggests the potential utility of cisplatin in combination with immunotherapy. A recent study showed that platinum-based chemotherapy synergizes with ErbB-targeted CAR-T cells, significantly reducing the tumor burden in mice, while co-treatment with the pharmacological autophagy inhibitor 3-MA caused a reversal in tumor cell suppression [186]. These results suggest a requirement for autophagy for the effectiveness of platinum-based chemotherapeutic agents, which argues against the strategy of autophagy inhibition.
Other studies, however, have suggested the necessity for autophagy inhibition in the utility of cisplatin with respect to the immune response. The tumor microenvironment is critical for chemotherapy efficacy where, for example, the polarization of tumor-associated macrophages (TAMs) influences tumor growth. Guo et al. found that the inhibition of autophagy using CQ would promote the polarization of tumor-associated macrophages to the M1 type, with an inhibitory effect on tumor proliferation and enhanced chemosensitivity of cisplatin [151]. LC3-associated phagocytosis (LAP) is a non-canonical autophagy that would be detected during phagocytosis by macrophages [187]. Recent studies have shown that blocking LAP inhibits the M2 type polarization of TAMs (a pro-tumoral proliferative state) and delays melanoma growth in vivo and in vitro [188]. These studies imply that the two-sided role of autophagy in the immune system is closely related to the timing of tumor development and furthermore that autophagy inhibition at a late stage of tumorigenesis might facilitate cisplatin activity.

5. Summary

Is autophagy always a barrier to cisplatin therapy? The currently available data indicate that the answer is nuanced and still uncertain. In general, the combination of autophagy inhibitors and cisplatin appears to have therapeutic potential for cisplatin-resistant tumors, but this approach likely cannot be generalized to cisplatin-sensitive tumors. With very few exceptions, the ongoing clinical trials of autophagy inhibition combined with cancer therapeutics have not yielded encouraging outcomes. Some fundamental reasons for this include that it has not been demonstrated conclusively that autophagy is consistently induced in malignancies by chemotherapy or radiation. Further, even if this were to be the case, there is no current approach that might indicate the nature of the induced autophagy. In addition, it is uncertain whether the tolerated dose of HCQ actually inhibits chemotherapy and radiation-induced autophagy and, if so, to what extent.
A clinical trial exploring the efficacy of combining CQ with cisplatin-etoposide in small-cell lung cancer (SCLC) patients was terminated 3 years after the initiation of the trial because of poor accrual (NCT00969306). Another clinical trial of CQ combined with cisplatin-etoposide for SCLC is currently ongoing in the Netherlands (EUCTR2009-014772-22-NL).
In addition to the reservations indicated above, how autophagy might influence the function of normal tissues such as the kidney (as indicated above), the GI tract where autophagy maintains integrity, or the central nervous system, wherein defective autophagy has been implicated in a number of pathological conditions, has generally not been given adequate consideration. Finally, the somewhat contradictory and still incomplete data relating to the influence of autophagy modulation on immune function with regard to tumor suppression indicates that we are not yet at a point where autophagy inhibition should be considered a viable clinical strategy in cancer therapeutics, whether in combination with cisplatin or other antitumor drugs or radiation.

Author Contributions

Conceptualization, J.X. and D.A.G.; Writing—original draft preparation, J.X.; writing—review and editing, D.A.G. All authors have read and agreed to the published version of the manuscript.

Funding

J.X. was financially supported by the National Natural Science Foundation of China, No. 81903854. Studies in Gewirtz’s laboratory relating to autophagy were supported by a grant from the Department of Defense Breast Cancer Research Program W81XWH-19-1-0490.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

3-MA: 3-methyladenine; AMBRA1: activating molecule in Beclin1-regulated autophagy; APE1: apurinic/apyrimidinic endonuclease 1; ATG: autophagy-related; ATM: ataxia telangiectasia mutated protein; ATR: ataxia telangiectasia- and RAD3-related protein; CDKs: cyclin-dependent kinases; CQ: chloroquine; ECRG4: esophageal carcinoma-related gene 4; HCQ: hydroxychloroquine; MAP1S: microtubule-associated protein 1s; MDM2: murine double minute 2; MMR: mismatch repair; OPSCC: oropharyngeal squamous cell carcinoma; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme; RASSF1A: RAS association domain containing family 1A; ROS: reactive oxygen species; TAMs: tumor-associated macrophages.

References

  1. Ghosh, S. Cisplatin: The first metal based anticancer drug. Bioorg. Chem. 2019, 88, 102925. [Google Scholar] [CrossRef]
  2. Chen, S.H.; Chang, J.Y. New Insights into Mechanisms of Cisplatin Resistance: From Tumor Cell to Microenvironment. Int. J. Mol. Sci. 2019, 20, 4136. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Rosenberg, B.; Van Camp, L.; Grimley, E.B.; Thomson, A.J. The inhibition of growth or cell division in Escherichia coli by different ionic species of platinum(IV) complexes. J. Biol. Chem. 1967, 242, 1347–1352. [Google Scholar] [CrossRef]
  4. Rosenberg, B.; VanCamp, L.; Trosko, J.E.; Mansour, V.H. Platinum compounds: A new class of potent antitumour agents. Nature 1969, 222, 385–386. [Google Scholar] [CrossRef] [PubMed]
  5. Hill, J.M.; Loeb, E.; MacLellan, A.; Hill, N.O.; Khan, A.; King, J.J. Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases. Cancer Chemother. Rep. 1975, 59, 647–659. [Google Scholar] [PubMed]
  6. Santos, N.; Ferreira, R.S.; Santos, A.C.D. Overview of cisplatin-induced neurotoxicity and ototoxicity, and the protective agents. Food Chem. Toxicol. 2020, 136, 111079. [Google Scholar] [CrossRef]
  7. Johnson, S.W.; Laub, P.B.; Beesley, J.S.; Ozols, R.F.; Hamilton, T.C. Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines. Cancer Res. 1997, 57, 850–856. [Google Scholar] [PubMed]
  8. Galluzzi, L.; Senovilla, L.; Vitale, I.; Michels, J.; Martins, I.; Kepp, O.; Castedo, M.; Kroemer, G. Molecular mechanisms of cisplatin resistance. Oncogene 2012, 31, 1869–1883. [Google Scholar] [CrossRef] [PubMed][Green Version]
  9. Kartalou, M.; Essigmann, J.M. Recognition of cisplatin adducts by cellular proteins. Mutat. Res. 2001, 478, 1–21. [Google Scholar] [CrossRef]
  10. Danford, A.J.; Wang, D.; Wang, Q.; Tullius, T.D.; Lippard, S.J. Platinum anticancer drug damage enforces a particular rotational setting of DNA in nucleosomes. Proc. Natl. Acad. Sci. USA 2005, 102, 12311–12316. [Google Scholar] [CrossRef][Green Version]
  11. Jung, Y.; Lippard, S.J. Direct cellular responses to platinum-induced DNA damage. Chem. Rev. 2007, 107, 1387–1407. [Google Scholar] [CrossRef]
  12. Wynne, P.; Newton, C.; Ledermann, J.A.; Olaitan, A.; Mould, T.A.; Hartley, J.A. Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy. Br. J. Cancer 2007, 97, 927–933. [Google Scholar] [CrossRef] [PubMed][Green Version]
  13. Makovec, T. Cisplatin and beyond: Molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol. Oncol. 2019, 53, 148–158. [Google Scholar] [CrossRef] [PubMed][Green Version]
  14. Boulikas, T.; Vougiouka, M. Cisplatin and platinum drugs at the molecular level. (Review). Oncol. Rep. 2003, 10, 1663–1682. [Google Scholar] [CrossRef] [PubMed]
  15. Dasari, S.; Tchounwou, P.B. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol. 2014, 740, 364–378. [Google Scholar] [CrossRef][Green Version]
  16. Fuertes, M.A.; Castilla, J.; Alonso, C.; Perez, J.M. Cisplatin biochemical mechanism of action: From cytotoxicity to induction of cell death through interconnections between apoptotic and necrotic pathways. Curr. Med. Chem. 2003, 10, 257–266. [Google Scholar] [CrossRef] [PubMed]
  17. Kim, R.; Tanabe, K.; Uchida, Y.; Emi, M.; Inoue, H.; Toge, T. Current status of the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother. Pharm. 2002, 50, 343–352. [Google Scholar] [CrossRef]
  18. Bai, L.; Wang, S. Targeting apoptosis pathways for new cancer therapeutics. Annu. Rev. Med. 2014, 65, 139–155. [Google Scholar] [CrossRef] [PubMed]
  19. Tchounwou, P.B.; Dasari, S.; Noubissi, F.K.; Ray, P.; Kumar, S. Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy. J. Exp. Pharmacol. 2021, 13, 303–328. [Google Scholar] [CrossRef] [PubMed]
  20. Koberle, B.; Grimaldi, K.A.; Sunters, A.; Hartley, J.A.; Kelland, L.R.; Masters, J.R. DNA repair capacity and cisplatin sensitivity of human testis tumour cells. Int. J. Cancer. J. Int. Du Cancer 1997, 70, 551–555. [Google Scholar] [CrossRef]
  21. Basu, A.; Krishnamurthy, S. Cellular responses to Cisplatin-induced DNA damage. J. Nucleic Acids 2010, 2010, 201367. [Google Scholar] [CrossRef][Green Version]
  22. Zhou, J.; Kang, Y.; Chen, L.; Wang, H.; Liu, J.; Zeng, S.; Yu, L. The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents. Front. Pharmacol. 2020, 11, 343. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. DeHaan, R.D.; Yazlovitskaya, E.M.; Persons, D.L. Regulation of p53 target gene expression by cisplatin-induced extracellular signal-regulated kinase. Cancer Chemother. Pharm. 2001, 48, 383–388. [Google Scholar] [CrossRef] [PubMed]
  24. Basu, A.; Tu, H. Activation of ERK during DNA damage-induced apoptosis involves protein kinase Cdelta. Biochem. Biophys. Res. Commun. 2005, 334, 1068–1073. [Google Scholar] [CrossRef] [PubMed]
  25. Peng, D.J.; Wang, J.; Zhou, J.Y.; Wu, G.S. Role of the Akt/mTOR survival pathway in cisplatin resistance in ovarian cancer cells. Biochem. Biophys. Res. Commun. 2010, 394, 600–605. [Google Scholar] [CrossRef] [PubMed][Green Version]
  26. Mizushima, N.; Komatsu, M. Autophagy: Renovation of cells and tissues. Cell 2011, 147, 728–741. [Google Scholar] [CrossRef] [PubMed][Green Version]
  27. Xie, Z.; Klionsky, D.J. Autophagosome formation: Core machinery and adaptations. Nat. Cell Biol. 2007, 9, 1102–1109. [Google Scholar] [CrossRef] [PubMed]
  28. Gasiorkiewicz, B.M.; Koczurkiewicz-Adamczyk, P.; Piska, K.; Pekala, E. Autophagy modulating agents as chemosensitizers for cisplatin therapy in cancer. Investig. New Drugs 2021, 39, 538–563. [Google Scholar] [CrossRef] [PubMed]
  29. Yu, L.; Gu, C.; Zhong, D.; Shi, L.; Kong, Y.; Zhou, Z.; Liu, S. Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance. Cancer Lett. 2014, 355, 34–45. [Google Scholar] [CrossRef]
  30. Gao, J.; Wang, W. Knockdown of galectin-1 facilitated cisplatin sensitivity by inhibiting autophagy in neuroblastoma cells. Chem.-Biol. Interact. 2019, 297, 50–56. [Google Scholar] [CrossRef]
  31. Wang, Z.; Liu, G.; Jiang, J. Profiling of apoptosis- and autophagy-associated molecules in human lung cancer A549 cells in response to cisplatin treatment using stable isotope labeling with amino acids in cell culture. Int. J. Oncol. 2019, 54, 1071–1085. [Google Scholar] [CrossRef] [PubMed][Green Version]
  32. Hernandez-Segura, A.; Nehme, J.; Demaria, M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018, 28, 436–453. [Google Scholar] [CrossRef]
  33. Saleh, T.; Bloukh, S.; Carpenter, V.J.; Alwohoush, E.; Bakeer, J.; Darwish, S.; Azab, B.; Gewirtz, D.A. Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy. Cancers 2020, 12, 822. [Google Scholar] [CrossRef] [PubMed][Green Version]
  34. Kasahara, K.; Fujiwara, Y.; Nishio, K.; Ohmori, T.; Sugimoto, Y.; Komiya, K.; Matsuda, T.; Saijo, N. Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Res. 1991, 51, 3237–3242. [Google Scholar] [PubMed]
  35. Safaei, R.; Katano, K.; Larson, B.J.; Samimi, G.; Holzer, A.K.; Naerdemann, W.; Tomioka, M.; Goodman, M.; Howell, S.B. Intracellular localization and trafficking of fluorescein-labeled cisplatin in human ovarian carcinoma cells. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2005, 11, 756–767. [Google Scholar]
  36. Sancho-Martinez, S.M.; Prieto-Garcia, L.; Prieto, M.; Lopez-Novoa, J.M.; Lopez-Hernandez, F.J. Subcellular targets of cisplatin cytotoxicity: An integrated view. Pharmacol. Ther. 2012, 136, 35–55. [Google Scholar] [CrossRef] [PubMed]
  37. Chauhan, S.S.; Liang, X.J.; Su, A.W.; Pai-Panandiker, A.; Shen, D.W.; Hanover, J.A.; Gottesman, M.M. Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines. Br. J. Cancer 2003, 88, 1327–1334. [Google Scholar] [CrossRef] [PubMed][Green Version]
  38. Safaei, R.; Howell, S.B. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit. Rev. Oncol./Hematol. 2005, 53, 13–23. [Google Scholar] [CrossRef]
  39. Liang, X.J.; Shen, D.W.; Garfield, S.; Gottesman, M.M. Mislocalization of membrane proteins associated with multidrug resistance in cisplatin-resistant cancer cell lines. Cancer Res. 2003, 63, 5909–5916. [Google Scholar] [PubMed]
  40. Petruzzelli, R.; Polishchuk, R.S. Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs. Cells 2019, 8, 1080. [Google Scholar] [CrossRef] [PubMed][Green Version]
  41. Vaisman, A.; Varchenko, M.; Umar, A.; Kunkel, T.A.; Risinger, J.I.; Barrett, J.C.; Hamilton, T.C.; Chaney, S.G. The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: Correlation with replicative bypass of platinum-DNA adducts. Cancer Res. 1998, 58, 3579–3585. [Google Scholar]
  42. Lowe, S.W.; Ruley, H.E.; Jacks, T.; Housman, D.E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993, 74, 957–967. [Google Scholar] [CrossRef]
  43. Bragado, P.; Armesilla, A.; Silva, A.; Porras, A. Apoptosis by cisplatin requires p53 mediated p38alpha MAPK activation through ROS generation. Apoptosis 2007, 12, 1733–1742. [Google Scholar] [CrossRef] [PubMed]
  44. Crook, T.; Parker, G.A.; Rozycka, M.; Crossland, S.; Allday, M.J. A transforming p53 mutant, which binds DNA, transactivates and induces apoptosis reveals a nuclear:cytoplasmic shuttling defect. Oncogene 1998, 16, 1429–1441. [Google Scholar] [CrossRef][Green Version]
  45. Soussi, T. The p53 tumor suppressor gene: From molecular biology to clinical investigation. Ann. N. Y. Acad. Sci. 2000, 910, 121–137; discussion 137–139. [Google Scholar] [CrossRef] [PubMed]
  46. Tachibana, M.; Kawamata, H.; Fujimori, T.; Omotehara, F.; Horiuchi, H.; Ohkura, Y.; Igarashi, S.; Kotake, K.; Kubota, K. Dysfunction of p53 pathway in human colorectal cancer: Analysis of p53 gene mutation and the expression of the p53-associated factors p14ARF, p33ING1, p21WAF1 and MDM2. Int. J. Oncol. 2004, 25, 913–920. [Google Scholar] [PubMed]
  47. Jahnson, S.; Karlsson, M.G. Tumor mapping of regional immunostaining for p21, p53, and mdm2 in locally advanced bladder carcinoma. Cancer 2000, 89, 619–629. [Google Scholar] [CrossRef]
  48. Gewirtz, D.A. The four faces of autophagy: Implications for cancer therapy. Cancer Res. 2014, 74, 647–651. [Google Scholar] [CrossRef] [PubMed][Green Version]
  49. Zhu, L.; Zhu, Y.; Han, S.; Chen, M.; Song, P.; Dai, D.; Xu, W.; Jiang, T.; Feng, L.; Shin, V.Y.; et al. Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer. Cell Death Dis. 2019, 10, 383. [Google Scholar] [CrossRef]
  50. Patel, N.H.; Xu, J.; Saleh, T.; Wu, Y.; Lima, S.; Gewirtz, D.A. Influence of nonprotective autophagy and the autophagic switch on sensitivity to cisplatin in non-small cell lung cancer cells. Biochem Pharm. 2020, 175, 113896. [Google Scholar] [CrossRef] [PubMed]
  51. Gewirtz, D.A. An autophagic switch in the response of tumor cells to radiation and chemotherapy. Biochem Pharm. 2014, 90, 208–211. [Google Scholar] [CrossRef] [PubMed]
  52. Chakradeo, S.; Sharma, K.; Alhaddad, A.; Bakhshwin, D.; Le, N.; Harada, H.; Nakajima, W.; Yeudall, W.A.; Torti, S.V.; Torti, F.M.; et al. Yet another function of p53--the switch that determines whether radiation-induced autophagy will be cytoprotective or nonprotective: Implications for autophagy inhibition as a therapeutic strategy. Mol. Pharmacol. 2015, 87, 803–814. [Google Scholar] [CrossRef] [PubMed][Green Version]
  53. Wilson, E.N.; Bristol, M.L.; Di, X.; Maltese, W.A.; Koterba, K.; Beckman, M.J.; Gewirtz, D.A. A switch between cytoprotective and cytotoxic autophagy in the radiosensitization of breast tumor cells by chloroquine and vitamin D. Horm. Cancer 2011, 2, 272–285. [Google Scholar] [CrossRef][Green Version]
  54. Shen, P.; Chen, M.; He, M.; Chen, L.; Song, Y.; Xiao, P.; Wan, X.; Dai, F.; Pan, T.; Wang, Q. Inhibition of ERalpha/ERK/P62 cascades induces “autophagic switch” in the estrogen receptor-positive breast cancer cells exposed to gemcitabine. Oncotarget 2016, 7, 48501–48516. [Google Scholar] [CrossRef]
  55. Reinhardt, H.C.; Aslanian, A.S.; Lees, J.A.; Yaffe, M.B. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 2007, 11, 175–189. [Google Scholar] [CrossRef] [PubMed][Green Version]
  56. Chen, Y.; Wu, J.; Liang, G.; Geng, G.; Zhao, F.; Yin, P.; Nowsheen, S.; Wu, C.; Li, Y.; Li, L.; et al. CHK2-FOXK axis promotes transcriptional control of autophagy programs. Sci. Adv. 2020, 6, eaax5819. [Google Scholar] [CrossRef] [PubMed][Green Version]
  57. Gomes, L.R.; Rocha, C.R.R.; Martins, D.J.; Fiore, A.; Kinker, G.S.; Bruni-Cardoso, A.; Menck, C.F.M. ATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulation. Cell Death Dis. 2019, 10, 459. [Google Scholar] [CrossRef] [PubMed]
  58. Cianfanelli, V.; Fuoco, C.; Lorente, M.; Salazar, M.; Quondamatteo, F.; Gherardini, P.F.; De Zio, D.; Nazio, F.; Antonioli, M.; D’Orazio, M.; et al. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat. Cell Biol. 2015, 17, 20–30. [Google Scholar] [CrossRef][Green Version]
  59. Antonioli, M.; Di Rienzo, M.; Piacentini, M.; Fimia, G.M. Emerging Mechanisms in Initiating and Terminating Autophagy. Trends Biochem. Sci. 2017, 42, 28–41. [Google Scholar] [CrossRef]
  60. Liu, J.; Chen, Z.; Guo, J.; Wang, L.; Liu, X. Ambra1 induces autophagy and desensitizes human prostate cancer cells to cisplatin. Biosci. Rep. 2019, 39. [Google Scholar] [CrossRef] [PubMed][Green Version]
  61. Li, X.; Zhang, L.; Yu, L.; Wei, W.; Lin, X.; Hou, X.; Tian, Y. shRNA-mediated AMBRA1 knockdown reduces the cisplatin-induced autophagy and sensitizes ovarian cancer cells to cisplatin. J. Toxicol. Sci. 2016, 41, 45–53. [Google Scholar] [CrossRef] [PubMed][Green Version]
  62. Antonioli, M.; Pagni, B.; Vescovo, T.; Ellis, R.; Cosway, B.; Rollo, F.; Bordoni, V.; Agrati, C.; Labus, M.; Covello, R.; et al. HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1. Autophagy 2021, 17, 2842–2855. [Google Scholar] [CrossRef] [PubMed]
  63. Shih, T.C.; Fan, Y.; Kiss, S.; Li, X.; Deng, X.N.; Liu, R.; Chen, X.J.; Carney, R.; Chen, A.; Ghosh, P.M.; et al. Galectin-1 inhibition induces cell apoptosis through dual suppression of CXCR4 and Ras pathways in human malignant peripheral nerve sheath tumors. Neuro-oncology 2019, 21, 1389–1400. [Google Scholar] [CrossRef] [PubMed]
  64. Seyrek, K.; Richter, M.; Lavrik, I.N. Decoding the sweet regulation of apoptosis: The role of glycosylation and galectins in apoptotic signaling pathways. Cell Death Differ. 2019, 26, 981–993. [Google Scholar] [CrossRef] [PubMed]
  65. Vladoiu, M.C.; Labrie, M.; St-Pierre, Y. Intracellular galectins in cancer cells: Potential new targets for therapy (Review). Int. J. Oncol. 2014, 44, 1001–1014. [Google Scholar] [CrossRef] [PubMed][Green Version]
  66. Chung, L.Y.; Tang, S.J.; Sun, G.H.; Chou, T.Y.; Yeh, T.S.; Yu, S.L.; Sun, K.H. Galectin-1 promotes lung cancer progression and chemoresistance by upregulating p38 MAPK, ERK, and cyclooxygenase-2. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2012, 18, 4037–4047. [Google Scholar] [CrossRef][Green Version]
  67. Zhu, H.; Chen, A.; Li, S.; Tao, X.; Sheng, B.; Chetry, M.; Zhu, X. Predictive role of galectin-1 and integrin alpha5beta1 in cisplatin-based neoadjuvant chemotherapy of bulky squamous cervical cancer. Biosci. Rep. 2017, 37, BSR20170958. [Google Scholar] [CrossRef] [PubMed][Green Version]
  68. Zhang, P.; Zhang, P.; Shi, B.; Zhou, M.; Jiang, H.; Zhang, H.; Pan, X.; Gao, H.; Sun, H.; Li, Z. Galectin-1 overexpression promotes progression and chemoresistance to cisplatin in epithelial ovarian cancer. Cell Death Dis. 2014, 5, e991. [Google Scholar] [CrossRef] [PubMed][Green Version]
  69. Su, Y.C.; Davuluri, G.V.; Chen, C.H.; Shiau, D.C.; Chen, C.C.; Chen, C.L.; Lin, Y.S.; Chang, C.P. Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma. PLoS ONE 2016, 11, e0148408. [Google Scholar] [CrossRef] [PubMed]
  70. Feng, W.; Marquez, R.T.; Lu, Z.; Liu, J.; Lu, K.H.; Issa, J.P.; Fishman, D.M.; Yu, Y.; Bast, R.C., Jr. Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer 2008, 112, 1489–1502. [Google Scholar] [CrossRef] [PubMed]
  71. Huang, S.; Chang, I.S.; Lin, W.; Ye, W.; Luo, R.Z.; Lu, Z.; Lu, Y.; Zhang, K.; Liao, W.S.; Tao, T.; et al. ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Biosci. Rep. 2009, 30, 159–168. [Google Scholar] [CrossRef] [PubMed][Green Version]
  72. Luo, R.Z.; Fang, X.; Marquez, R.; Liu, S.Y.; Mills, G.B.; Liao, W.S.; Yu, Y.; Bast, R.C. ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers. Oncogene 2003, 22, 2897–2909. [Google Scholar] [CrossRef] [PubMed][Green Version]
  73. Badgwell, D.B.; Lu, Z.; Le, K.; Gao, F.; Yang, M.; Suh, G.K.; Bao, J.J.; Das, P.; Andreeff, M.; Chen, W.; et al. The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways. Oncogene 2012, 31, 68–79. [Google Scholar] [CrossRef] [PubMed][Green Version]
  74. Lu, Z.; Yang, H.; Sutton, M.N.; Yang, M.; Clarke, C.H.; Liao, W.S.; Bast, R.C., Jr. ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7. Cell Death Differ. 2014, 21, 1275–1289. [Google Scholar] [CrossRef][Green Version]
  75. Lu, Z.; Luo, R.Z.; Lu, Y.; Zhang, X.; Yu, Q.; Khare, S.; Kondo, S.; Kondo, Y.; Yu, Y.; Mills, G.B.; et al. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J. Clin. Investig. 2008, 118, 3917–3929. [Google Scholar] [CrossRef] [PubMed][Green Version]
  76. Li, J.; Cui, G.; Sun, L.; Wang, S.J.; Tian, S.; Guan, Z.; Fan, W.S.; Yan, Z.F.; Yang, Y.Z.; You, Y.Q.; et al. ARHI overexpression induces epithelial ovarian cancer cell apoptosis and excessive autophagy. Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 2014, 24, 437–443. [Google Scholar] [CrossRef] [PubMed]
  77. Washington, M.N.; Suh, G.; Orozco, A.F.; Sutton, M.N.; Yang, H.; Wang, Y.; Mao, W.; Millward, S.; Ornelas, A.; Atkinson, N.; et al. ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts. Cell Death Dis. 2015, 6, e1836. [Google Scholar] [CrossRef] [PubMed][Green Version]
  78. Gotze, S.; Feldhaus, V.; Traska, T.; Wolter, M.; Reifenberger, G.; Tannapfel, A.; Kuhnen, C.; Martin, D.; Muller, O.; Sievers, S. ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma. BMC Cancer 2009, 9, 447. [Google Scholar] [CrossRef] [PubMed][Green Version]
  79. Liang, X.; Gao, J.; Wang, Q.; Hou, S.; Wu, C. ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-kappaB Signaling Pathway in Bladder Cancer. Front. Genet. 2020, 11, 846. [Google Scholar] [CrossRef] [PubMed]
  80. Chen, J.Y.; Wu, X.; Hong, C.Q.; Chen, J.; Wei, X.L.; Zhou, L.; Zhang, H.X.; Huang, Y.T.; Peng, L. Downregulated ECRG4 is correlated with lymph node metastasis and predicts poor outcome for nasopharyngeal carcinoma patients. Clin. Transl. Oncol. Off. Publ. Fed. Span. Oncol. Soc. Natl. Cancer Inst. Mex. 2017, 19, 84–90. [Google Scholar] [CrossRef]
  81. Lee, J.; Dang, X.; Borboa, A.; Coimbra, R.; Baird, A.; Eliceiri, B.P. Thrombin-processed Ecrg4 recruits myeloid cells and induces antitumorigenic inflammation. Neuro-Oncol. 2015, 17, 685–696. [Google Scholar] [CrossRef] [PubMed][Green Version]
  82. You, Y.; Yang, W.; Qin, X.; Wang, F.; Li, H.; Lin, C.; Li, W.; Gu, C.; Zhang, Y.; Ran, Y. ECRG4 acts as a tumor suppressor and as a determinant of chemotherapy resistance in human nasopharyngeal carcinoma. Cell. Oncol. 2015, 38, 205–214. [Google Scholar] [CrossRef] [PubMed]
  83. Abdel-Wahab, A.F.; Mahmoud, W.; Al-Harizy, R.M. Targeting glucose metabolism to suppress cancer progression: Prospective of anti-glycolytic cancer therapy. Pharmacol. Res. Off. J. Ital. Pharmacol. Soc. 2019, 150, 104511. [Google Scholar] [CrossRef] [PubMed]
  84. Atsumi, T.; Chesney, J.; Metz, C.; Leng, L.; Donnelly, S.; Makita, Z.; Mitchell, R.; Bucala, R. High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. 2002, 62, 5881–5887. [Google Scholar] [PubMed]
  85. Li, H.M.; Yang, J.G.; Liu, Z.J.; Wang, W.M.; Yu, Z.L.; Ren, J.G.; Chen, G.; Zhang, W.; Jia, J. Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma. J. Exp. Clin. Cancer Res. CR 2017, 36, 7. [Google Scholar] [CrossRef] [PubMed][Green Version]
  86. Shi, W.K.; Zhu, X.D.; Wang, C.H.; Zhang, Y.Y.; Cai, H.; Li, X.L.; Cao, M.Q.; Zhang, S.Z.; Li, K.S.; Sun, H.C. PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT. Cell Death Dis. 2018, 9, 428. [Google Scholar] [CrossRef][Green Version]
  87. Minchenko, O.H.; Ochiai, A.; Opentanova, I.L.; Ogura, T.; Minchenko, D.O.; Caro, J.; Komisarenko, S.V.; Esumi, H. Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-4 in the human breast and colon malignant tumors. Biochimie 2005, 87, 1005–1010. [Google Scholar] [CrossRef]
  88. Bobarykina, A.Y.; Minchenko, D.O.; Opentanova, I.L.; Moenner, M.; Caro, J.; Esumi, H.; Minchenko, O.H. Hypoxic regulation of PFKFB-3 and PFKFB-4 gene expression in gastric and pancreatic cancer cell lines and expression of PFKFB genes in gastric cancers. Acta Biochim. Pol. 2006, 53, 789–799. [Google Scholar] [CrossRef] [PubMed][Green Version]
  89. Mondal, S.; Roy, D.; Sarkar Bhattacharya, S.; Jin, L.; Jung, D.; Zhang, S.; Kalogera, E.; Staub, J.; Wang, Y.; Xuyang, W.; et al. Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. Int. J. Cancer. J. Int. Du Cancer 2019, 144, 178–189. [Google Scholar] [CrossRef][Green Version]
  90. Cantelmo, A.R.; Conradi, L.C.; Brajic, A.; Goveia, J.; Kalucka, J.; Pircher, A.; Chaturvedi, P.; Hol, J.; Thienpont, B.; Teuwen, L.A.; et al. Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell 2016, 30, 968–985. [Google Scholar] [CrossRef][Green Version]
  91. Li, F.L.; Liu, J.P.; Bao, R.X.; Yan, G.; Feng, X.; Xu, Y.P.; Sun, Y.P.; Yan, W.; Ling, Z.Q.; Xiong, Y.; et al. Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis. Nat. Commun. 2018, 9, 508. [Google Scholar] [CrossRef][Green Version]
  92. Xiao, Y.; Jin, L.; Deng, C.; Guan, Y.; Kalogera, E.; Ray, U.; Thirusangu, P.; Staub, J.; Sarkar Bhattacharya, S.; Xu, H.; et al. Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer. Oncogene 2021, 40, 1409–1424. [Google Scholar] [CrossRef] [PubMed]
  93. Tung, M.C.; Lin, P.L.; Wang, Y.C.; He, T.Y.; Lee, M.C.; Yeh, S.D.; Chen, C.Y.; Lee, H. Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2. Oncotarget 2015, 6, 41692–41705. [Google Scholar] [CrossRef] [PubMed]
  94. Lavarino, C.; Pilotti, S.; Oggionni, M.; Gatti, L.; Perego, P.; Bresciani, G.; Pierotti, M.A.; Scambia, G.; Ferrandina, G.; Fagotti, A.; et al. p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2000, 18, 3936–3945. [Google Scholar] [CrossRef] [PubMed]
  95. Baltaci, S.; Orhan, D.; Turkolmez, K.; Yesilli, C.; Beduk, Y.; Tulunay, O. P53, bcl-2 and bax immunoreactivity as predictors of response and outcome after chemotherapy for metastatic germ cell testicular tumours. BJU Int. 2001, 87, 661–666. [Google Scholar] [CrossRef] [PubMed]
  96. Tasdemir, E.; Maiuri, M.C.; Galluzzi, L.; Vitale, I.; Djavaheri-Mergny, M.; D’Amelio, M.; Criollo, A.; Morselli, E.; Zhu, C.; Harper, F.; et al. Regulation of autophagy by cytoplasmic p53. Nat. Cell Biol. 2008, 10, 676–687. [Google Scholar] [CrossRef] [PubMed][Green Version]
  97. Zhang, X.; Qi, Z.; Yin, H.; Yang, G. Interaction between p53 and Ras signaling controls cisplatin resistance via HDAC4- and HIF-1alpha-mediated regulation of apoptosis and autophagy. Theranostics 2019, 9, 1096–1114. [Google Scholar] [CrossRef]
  98. Rosenfeldt, M.T.; O’Prey, J.; Morton, J.P.; Nixon, C.; MacKay, G.; Mrowinska, A.; Au, A.; Rai, T.S.; Zheng, L.; Ridgway, R.; et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 2013, 504, 296–300. [Google Scholar] [CrossRef] [PubMed]
  99. Tripathi, R.; Ash, D.; Shaha, C. Beclin-1-p53 interaction is crucial for cell fate determination in embryonal carcinoma cells. J. Cell. Mol. Med. 2014, 18, 2275–2286. [Google Scholar] [CrossRef]
  100. Maycotte, P.; Aryal, S.; Cummings, C.T.; Thorburn, J.; Morgan, M.J.; Thorburn, A. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy 2012, 8, 200–212. [Google Scholar] [CrossRef][Green Version]
  101. Yee, K.S.; Grochola, L.; Hamilton, G.; Grawenda, A.; Bond, E.E.; Taubert, H.; Wurl, P.; Bond, G.L.; O’Neill, E. A RASSF1A polymorphism restricts p53/p73 activation and associates with poor survival and accelerated age of onset of soft tissue sarcoma. Cancer Res. 2012, 72, 2206–2217. [Google Scholar] [CrossRef] [PubMed][Green Version]
  102. Koul, S.; McKiernan, J.M.; Narayan, G.; Houldsworth, J.; Bacik, J.; Dobrzynski, D.L.; Assaad, A.M.; Mansukhani, M.; Reuter, V.E.; Bosl, G.J.; et al. Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors. Mol Cancer 2004, 3, 16. [Google Scholar] [CrossRef] [PubMed][Green Version]
  103. de Fraipont, F.; Levallet, G.; Creveuil, C.; Bergot, E.; Beau-Faller, M.; Mounawar, M.; Richard, N.; Antoine, M.; Rouquette, I.; Favrot, M.C.; et al. An apoptosis methylation prognostic signature for early lung cancer in the IFCT-0002 trial. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2012, 18, 2976–2986. [Google Scholar] [CrossRef] [PubMed][Green Version]
  104. Levesley, J.; Lusher, M.E.; Lindsey, J.C.; Clifford, S.C.; Grundy, R.; Coyle, B. RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines. Neuro-Oncol. 2011, 13, 1265–1276. [Google Scholar] [CrossRef] [PubMed][Green Version]
  105. Wang, J.; Zhang, X.; Yang, F.; Yang, Y.; Wang, T.; Liu, W.; Zhou, H.; Zhao, W. RASSF1A Enhances Chemosensitivity of NSCLC Cells Through Activating Autophagy by Regulating MAP1S to Inactivate Keap1-Nrf2 Pathway. Drug Des. Dev. Ther. 2021, 15, 21–35. [Google Scholar] [CrossRef] [PubMed]
  106. Ando, K.; Hirao, S.; Kabe, Y.; Ogura, Y.; Sato, I.; Yamaguchi, Y.; Wada, T.; Handa, H. A new APE1/Ref-1-dependent pathway leading to reduction of NF-kappaB and AP-1, and activation of their DNA-binding activity. Nucleic Acids Res. 2008, 36, 4327–4336. [Google Scholar] [CrossRef] [PubMed][Green Version]
  107. Lando, D.; Pongratz, I.; Poellinger, L.; Whitelaw, M.L. A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1alpha and the HIF-like factor. J. Biol. Chem. 2000, 275, 4618–4627. [Google Scholar] [CrossRef] [PubMed][Green Version]
  108. Bhattacharyya, A.; Chattopadhyay, R.; Burnette, B.R.; Cross, J.V.; Mitra, S.; Ernst, P.B.; Bhakat, K.K.; Crowe, S.E. Acetylation of apurinic/apyrimidinic endonuclease-1 regulates Helicobacter pylori-mediated gastric epithelial cell apoptosis. Gastroenterology 2009, 136, 2258–2269. [Google Scholar] [CrossRef] [PubMed][Green Version]
  109. Cardoso, A.A.; Jiang, Y.; Luo, M.; Reed, A.M.; Shahda, S.; He, Y.; Maitra, A.; Kelley, M.R.; Fishel, M.L. APE1/Ref-1 regulates STAT3 transcriptional activity and APE1/Ref-1-STAT3 dual-targeting effectively inhibits pancreatic cancer cell survival. PLoS ONE 2012, 7, e47462. [Google Scholar] [CrossRef] [PubMed]
  110. Fishel, M.L.; Wu, X.; Devlin, C.M.; Logsdon, D.P.; Jiang, Y.; Luo, M.; He, Y.; Yu, Z.; Tong, Y.; Lipking, K.P.; et al. Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) redox function negatively regulates NRF2. J. Biol. Chem. 2015, 290, 3057–3068. [Google Scholar] [CrossRef] [PubMed][Green Version]
  111. Wang, D.; Xiang, D.B.; Yang, X.Q.; Chen, L.S.; Li, M.X.; Zhong, Z.Y.; Zhang, Y.S. APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE1 enhances the activity of cisplatin in A549 cells. Lung Cancer 2009, 66, 298–304. [Google Scholar] [CrossRef] [PubMed]
  112. Manguinhas, R.; Fernandes, A.S.; Costa, J.G.; Saraiva, N.; Camoes, S.P.; Gil, N.; Rosell, R.; Castro, M.; Miranda, J.P.; Oliveira, N.G. Impact of the APE1 Redox Function Inhibitor E3330 in Non-small Cell Lung Cancer Cells Exposed to Cisplatin: Increased Cytotoxicity and Impairment of Cell Migration and Invasion. Antioxidants 2020, 9, 550. [Google Scholar] [CrossRef] [PubMed]
  113. Peng, Y.; Li, Z.; Zhang, S.; Xiong, Y.; Cun, Y.; Qian, C.; Li, M.; Ren, T.; Xia, L.; Cheng, Y.; et al. Association of DNA base excision repair genes (OGG1, APE1 and XRCC1) polymorphisms with outcome to platinum-based chemotherapy in advanced nonsmall-cell lung cancer patients. Int. J. Cancer. J. Int. Du Cancer 2014, 135, 2687–2696. [Google Scholar] [CrossRef] [PubMed]
  114. Tell, G.; Fantini, D.; Quadrifoglio, F. Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment. Cell. Mol. Life Sci. CMLS 2010, 67, 3589–3608. [Google Scholar] [CrossRef]
  115. Li, Z.; Wang, Y.; Wu, L.; Dong, Y.; Zhang, J.; Chen, F.; Xie, W.; Huang, J.; Lu, N. Apurinic endonuclease 1 promotes the cisplatin resistance of lung cancer cells by inducing Parkinmediated mitophagy. Oncol. Rep. 2019, 42, 2245–2254. [Google Scholar] [CrossRef] [PubMed]
  116. Pan, S.T.; Zhou, J.; Yang, F.; Zhou, S.F.; Ren, T. Proteomics reveals a therapeutic vulnerability via the combined blockade of APE1 and autophagy in lung cancer A549 cells. BMC Cancer 2020, 20, 634. [Google Scholar] [CrossRef] [PubMed]
  117. Latorre, E.; Carelli, S.; Raimondi, I.; D’Agostino, V.; Castiglioni, I.; Zucal, C.; Moro, G.; Luciani, A.; Ghilardi, G.; Monti, E.; et al. The Ribonucleic Complex HuR-MALAT1 Represses CD133 Expression and Suppresses Epithelial-Mesenchymal Transition in Breast Cancer. Cancer Res. 2016, 76, 2626–2636. [Google Scholar] [CrossRef] [PubMed][Green Version]
  118. YiRen, H.; YingCong, Y.; Sunwu, Y.; Keqin, L.; Xiaochun, T.; Senrui, C.; Ende, C.; XiZhou, L.; Yanfan, C. Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer. Mol. Cancer 2017, 16, 174. [Google Scholar] [CrossRef][Green Version]
  119. Xi, Z.; Si, J.; Nan, J. LncRNA MALAT1 potentiates autophagyassociated cisplatin resistance by regulating the microRNA30b/autophagyrelated gene 5 axis in gastric cancer. Int. J. Oncol. 2019, 54, 239–248. [Google Scholar] [CrossRef] [PubMed][Green Version]
  120. Zhang, Y.F.; Li, C.S.; Zhou, Y.; Lu, X.H. Propofol facilitates cisplatin sensitivity via lncRNA MALAT1/miR-30e/ATG5 axis through suppressing autophagy in gastric cancer. Life Sci. 2020, 244, 117280. [Google Scholar] [CrossRef] [PubMed]
  121. Peng, L.; Sang, H.; Wei, S.; Li, Y.; Jin, D.; Zhu, X.; Li, X.; Dang, Y.; Zhang, G. circCUL2 regulates gastric cancer malignant transformation and cisplatin resistance by modulating autophagy activation via miR-142-3p/ROCK2. Mol. Cancer 2020, 19, 156. [Google Scholar] [CrossRef] [PubMed]
  122. Li, B.; Wang, W.; Li, Z.; Chen, Z.; Zhi, X.; Xu, J.; Li, Q.; Wang, L.; Huang, X.; Wang, L.; et al. MicroRNA-148a-3p enhances cisplatin cytotoxicity in gastric cancer through mitochondrial fission induction and cyto-protective autophagy suppression. Cancer Lett. 2017, 410, 212–227. [Google Scholar] [CrossRef]
  123. Zhao, R.; Zhang, X.; Zhang, Y.; Zhang, Y.; Yang, Y.; Sun, Y.; Zheng, X.; Qu, A.; Umwali, Y.; Zhang, Y. HOTTIP Predicts Poor Survival in Gastric Cancer Patients and Contributes to Cisplatin Resistance by Sponging miR-216a-5p. Front. Cell Dev. Biol. 2020, 8, 348. [Google Scholar] [CrossRef] [PubMed]
  124. Huang, F.X.; Chen, H.J.; Zheng, F.X.; Gao, Z.Y.; Sun, P.F.; Peng, Q.; Liu, Y.; Deng, X.; Huang, Y.H.; Zhao, C.; et al. LncRNA BLACAT1 is involved in chemoresistance of nonsmall cell lung cancer cells by regulating autophagy. Int. J. Oncol. 2019, 54, 339–347. [Google Scholar] [CrossRef][Green Version]
  125. Hua, L.; Zhu, G.; Wei, J. MicroRNA-1 overexpression increases chemosensitivity of non-small cell lung cancer cells by inhibiting autophagy related 3-mediated autophagy. Cell Biol. Int. 2018, 42, 1240–1249. [Google Scholar] [CrossRef] [PubMed]
  126. Liu, J.; Xing, Y.; Rong, L. miR-181 regulates cisplatin-resistant non-small cell lung cancer via downregulation of autophagy through the PTEN/PI3K/AKT pathway. Oncol. Rep. 2018, 39, 1631–1639. [Google Scholar] [CrossRef] [PubMed][Green Version]
  127. Wang, H.; Chen, J.; Zhang, S.; Zheng, X.; Xie, S.; Mao, J.; Cai, Y.; Lu, X.; Hu, L.; Shen, J.; et al. MiR-223 regulates autophagy associated with cisplatin resistance by targeting FBXW7 in human non-small cell lung cancer. Cancer Cell Int. 2020, 20, 258. [Google Scholar] [CrossRef] [PubMed]
  128. Ma, Y.; Yuwen, D.; Chen, J.; Zheng, B.; Gao, J.; Fan, M.; Xue, W.; Wang, Y.; Li, W.; Shu, Y.; et al. Exosomal Transfer of Cisplatin-Induced miR-425-3p Confers Cisplatin Resistance in NSCLC Through Activating Autophagy. Int. J. Nanomed. 2019, 14, 8121–8132. [Google Scholar] [CrossRef][Green Version]
  129. Wang, S.; Li, M.Y.; Liu, Y.; Vlantis, A.C.; Chan, J.Y.; Xue, L.; Hu, B.G.; Yang, S.; Chen, M.X.; Zhou, S.; et al. The role of microRNA in cisplatin resistance or sensitivity. Expert Opin. Ther. Targets 2020, 24, 885–897. [Google Scholar] [CrossRef] [PubMed]
  130. Wang, S.; Wu, J.; Ren, J.; Vlantis, A.C.; Li, M.Y.; Liu, S.Y.W.; Ng, E.K.W.; Chan, A.B.W.; Luo, D.C.; Liu, Z.; et al. MicroRNA-125b Interacts with Foxp3 to Induce Autophagy in Thyroid Cancer. Mol. Ther. J. Am. Soc. Gene Ther. 2018, 26, 2295–2303. [Google Scholar] [CrossRef][Green Version]
  131. Li, Y.; Hu, T.; Chen, T.; Yang, T.; Ren, H.; Chen, M. Combination treatment of FTY720 and cisplatin exhibits enhanced antitumour effects on cisplatin-resistant non-small lung cancer cells. Oncol. Rep. 2018, 39, 565–572. [Google Scholar] [CrossRef]
  132. Luo, L.; Sun, W.; Zhu, W.; Li, S.; Zhang, W.; Xu, X.; Fang, D.; Grahn, T.H.M.; Jiang, L.; Zheng, Y. BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism. Cell Death Dis. 2021, 12, 169. [Google Scholar] [CrossRef]
  133. Bai, Y.; Liu, X.; Qi, X.; Liu, X.; Peng, F.; Li, H.; Fu, H.; Pei, S.; Chen, L.; Chi, X.; et al. PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway. EBioMedicine 2019, 42, 311–325. [Google Scholar] [CrossRef] [PubMed][Green Version]
  134. Ranzuglia, V.; Lorenzon, I.; Pellarin, I.; Sonego, M.; Dall’Acqua, A.; D’Andrea, S.; Lovisa, S.; Segatto, I.; Coan, M.; Polesel, J.; et al. Serum- and glucocorticoid- inducible kinase 2, SGK2, is a novel autophagy regulator and modulates platinum drugs response in cancer cells. Oncogene 2020, 39, 6370–6386. [Google Scholar] [CrossRef] [PubMed]
  135. Meng, J.; Liu, K.; Shao, Y.; Feng, X.; Ji, Z.; Chang, B.; Wang, Y.; Xu, L.; Yang, G. ID1 confers cancer cell chemoresistance through STAT3/ATF6-mediated induction of autophagy. Cell Death Dis. 2020, 11, 137. [Google Scholar] [CrossRef] [PubMed][Green Version]
  136. Lei, Y.; Tang, L.; Hu, J.; Wang, S.; Liu, Y.; Yang, M.; Zhang, J.; Tang, B. Inhibition of MGMT-mediated autophagy suppression decreases cisplatin chemosensitivity in gastric cancer. Biomed. Pharmacother. Biomed. Pharmacother. 2020, 125, 109896. [Google Scholar] [CrossRef]
  137. Ma, H.; Li, Y.; Wang, X.; Wu, H.; Qi, G.; Li, R.; Yang, N.; Gao, M.; Yan, S.; Yuan, C.; et al. PBK, targeted by EVI1, promotes metastasis and confers cisplatin resistance through inducing autophagy in high-grade serous ovarian carcinoma. Cell Death Dis. 2019, 10, 166. [Google Scholar] [CrossRef]
  138. Takeda, T.; Komatsu, M.; Chiwaki, F.; Komatsuzaki, R.; Nakamura, K.; Tsuji, K.; Kobayashi, Y.; Tominaga, E.; Ono, M.; Banno, K.; et al. Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins. Cell Death Dis. 2019, 10, 876. [Google Scholar] [CrossRef]
  139. Liu, Y.; Fu, Y.; Hu, X.; Chen, S.; Miao, J.; Wang, Y.; Zhou, Y.; Zhang, Y. Caveolin-1 knockdown increases the therapeutic sensitivity of lung cancer to cisplatin-induced apoptosis by repressing Parkin-related mitophagy and activating the ROCK1 pathway. J. Cell. Physiol. 2020, 235, 1197–1208. [Google Scholar] [CrossRef] [PubMed]
  140. Xiao, X.; Wang, W.; Li, Y.; Yang, D.; Li, X.; Shen, C.; Liu, Y.; Ke, X.; Guo, S.; Guo, Z. HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma. J. Exp. Clin. Cancer Res. CR 2018, 37, 201. [Google Scholar] [CrossRef]
  141. Zhou, F.; Yang, X.; Zhao, H.; Liu, Y.; Feng, Y.; An, R.; Lv, X.; Li, J.; Chen, B. Down-regulation of OGT promotes cisplatin resistance by inducing autophagy in ovarian cancer. Theranostics 2018, 8, 5200–5212. [Google Scholar] [CrossRef]
  142. Monisha, J.; Roy, N.K.; Padmavathi, G.; Banik, K.; Bordoloi, D.; Khwairakpam, A.D.; Arfuso, F.; Chinnathambi, A.; Alahmadi, T.A.; Alharbi, S.A.; et al. NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration and Chemoresistance. Cancers 2018, 10, 228. [Google Scholar] [CrossRef][Green Version]
  143. Kim, M.; Jung, J.Y.; Choi, S.; Lee, H.; Morales, L.D.; Koh, J.T.; Kim, S.H.; Choi, Y.D.; Choi, C.; Slaga, T.J.; et al. GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy. Autophagy 2017, 13, 149–168. [Google Scholar] [CrossRef][Green Version]
  144. Homewood, C.A.; Warhurst, D.C.; Peters, W.; Baggaley, V.C. Lysosomes, pH and the anti-malarial action of chloroquine. Nature 1972, 235, 50–52. [Google Scholar] [CrossRef] [PubMed]
  145. Kimura, T.; Takabatake, Y.; Takahashi, A.; Isaka, Y. Chloroquine in cancer therapy: A double-edged sword of autophagy. Cancer Res. 2013, 73, 3–7. [Google Scholar] [CrossRef] [PubMed][Green Version]
  146. Circu, M.; Cardelli, J.; Barr, M.P.; O’Byrne, K.; Mills, G.; El-Osta, H. Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells. PLoS ONE 2017, 12, e0184922. [Google Scholar] [CrossRef] [PubMed][Green Version]
  147. Fukuda, T.; Oda, K.; Wada-Hiraike, O.; Sone, K.; Inaba, K.; Ikeda, Y.; Miyasaka, A.; Kashiyama, T.; Tanikawa, M.; Arimoto, T.; et al. The anti-malarial chloroquine suppresses proliferation and overcomes cisplatin resistance of endometrial cancer cells via autophagy inhibition. Gynecol. Oncol. 2015, 137, 538–545. [Google Scholar] [CrossRef] [PubMed]
  148. Schlutermann, D.; Skowron, M.A.; Berleth, N.; Bohler, P.; Deitersen, J.; Stuhldreier, F.; Wallot-Hieke, N.; Wu, W.; Peter, C.; Hoffmann, M.J.; et al. Targeting urothelial carcinoma cells by combining cisplatin with a specific inhibitor of the autophagy-inducing class III PtdIns3K complex. Urol. Oncol. 2018, 36, 160.e1–160.e13. [Google Scholar] [CrossRef]
  149. Hwang, J.R.; Kim, W.Y.; Cho, Y.J.; Ryu, J.Y.; Choi, J.J.; Jeong, S.Y.; Kim, M.S.; Kim, J.H.; Paik, E.S.; Lee, Y.Y.; et al. Chloroquine reverses chemoresistance via upregulation of p21(WAF1/CIP1) and autophagy inhibition in ovarian cancer. Cell Death Dis. 2020, 11, 1034. [Google Scholar] [CrossRef] [PubMed]
  150. Gunda, V.; Pathania, A.S.; Chava, S.; Prathipati, P.; Chaturvedi, N.K.; Coulter, D.W.; Pandey, M.K.; Durden, D.L.; Challagundla, K.B. Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma. Cancers 2020, 12, 2576. [Google Scholar] [CrossRef] [PubMed]
  151. Guo, Y.; Feng, Y.; Cui, X.; Wang, Q.; Pan, X. Autophagy inhibition induces the repolarisation of tumour-associated macrophages and enhances chemosensitivity of laryngeal cancer cells to cisplatin in mice. Cancer Immunol. Immunother. CII 2019, 68, 1909–1920. [Google Scholar] [CrossRef] [PubMed]
  152. Magnano, S.; Hannon Barroeta, P.; Duffy, R.; O’Sullivan, J.; Zisterer, D.M. Cisplatin induces autophagy-associated apoptosis in human oral squamous cell carcinoma (OSCC) mediated in part through reactive oxygen species. Toxicol. Appl. Pharm. 2021, 427, 115646. [Google Scholar] [CrossRef]
  153. Levy, J.M.; Thorburn, A. Modulation of pediatric brain tumor autophagy and chemosensitivity. J. Neuro-Oncol. 2012, 106, 281–290. [Google Scholar] [CrossRef] [PubMed][Green Version]
  154. Phoo, N.L.L.; Dejkriengkraikul, P.; Khaw-On, P.; Yodkeeree, S. Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death. Int. J. Mol. Sci. 2021, 22, 12512. [Google Scholar] [CrossRef]
  155. Wang, J.; Wu, G.S. Role of autophagy in cisplatin resistance in ovarian cancer cells. J. Biol. Chem. 2014, 289, 17163–17173. [Google Scholar] [CrossRef][Green Version]
  156. Ko, J.C.; Tsai, M.S.; Chiu, Y.F.; Weng, S.H.; Kuo, Y.H.; Lin, Y.W. Up-regulation of extracellular signal-regulated kinase 1/2-dependent thymidylate synthase and thymidine phosphorylase contributes to cisplatin resistance in human non-small-cell lung cancer cells. J. Pharmacol. Exp. Ther. 2011, 338, 184–194. [Google Scholar] [CrossRef]
  157. Lai, S.T.; Wang, Y.; Peng, F. Astragaloside IV sensitizes non-small cell lung cancer cells to cisplatin by suppressing endoplasmic reticulum stress and autophagy. J. Thorac. Dis. 2020, 12, 3715–3724. [Google Scholar] [CrossRef] [PubMed]
  158. Kim, H.I.; Hong, S.H.; Ku, J.M.; Kim, M.J.; Ju, S.W.; Chang, S.W.; Cheon, C.; Ko, S.G. Gardenia jasminoides Enhances CDDP-Induced Apoptosis of Glioblastoma Cells via AKT/mTOR Pathway While Protecting Death of Astrocytes. Nutrients 2020, 12, 196. [Google Scholar] [CrossRef] [PubMed][Green Version]
  159. Lin, Y.X.; Wang, Y.; An, H.W.; Qi, B.; Wang, J.; Wang, L.; Shi, J.; Mei, L.; Wang, H. Peptide-Based Autophagic Gene and Cisplatin Co-delivery Systems Enable Improved Chemotherapy Resistance. Nano Lett. 2019, 19, 2968–2978. [Google Scholar] [CrossRef] [PubMed]
  160. Li, Q.; Liu, X.; Yan, W.; Chen, Y. Antitumor effect of poly lactic acid nanoparticles loaded with cisplatin and chloroquine on the oral squamous cell carcinoma. Aging 2020, 13, 2593–2603. [Google Scholar] [CrossRef]
  161. Wang, K.; Liu, X.; Liu, Q.; Ho, I.H.; Wei, X.; Yin, T.; Zhan, Y.; Zhang, W.; Zhang, W.; Chen, B.; et al. Hederagenin potentiated cisplatin- and paclitaxel-mediated cytotoxicity by impairing autophagy in lung cancer cells. Cell Death Dis. 2020, 11, 611. [Google Scholar] [CrossRef] [PubMed]
  162. Lv, M.; Zhuang, X.; Zhang, Q.; Cheng, Y.; Wu, D.; Wang, X.; Qiao, T. Acetyl-11-keto-beta-boswellic acid enhances the cisplatin sensitivity of non-small cell lung cancer cells through cell cycle arrest, apoptosis induction, and autophagy suppression via p21-dependent signaling pathway. Cell Biol. Toxicol. 2021, 37, 209–228. [Google Scholar] [CrossRef]
  163. Mi, S.; Xiang, G.; Yuwen, D.; Gao, J.; Guo, W.; Wu, X.; Wu, X.; Sun, Y.; Su, Y.; Shen, Y.; et al. Inhibition of autophagy by andrographolide resensitizes cisplatin-resistant non-small cell lung carcinoma cells via activation of the Akt/mTOR pathway. Toxicol. Appl. Pharm. 2016, 310, 78–86. [Google Scholar] [CrossRef]
  164. Zhou, J.; Hu, S.E.; Tan, S.H.; Cao, R.; Chen, Y.; Xia, D.; Zhu, X.; Yang, X.F.; Ong, C.N.; Shen, H.M. Andrographolide sensitizes cisplatin-induced apoptosis via suppression of autophagosome-lysosome fusion in human cancer cells. Autophagy 2012, 8, 338–349. [Google Scholar] [CrossRef] [PubMed][Green Version]
  165. Pal Singh, M.; Pal Khaket, T.; Bajpai, V.K.; Alfarraj, S.; Kim, S.G.; Chen, L.; Huh, Y.S.; Han, Y.K.; Kang, S.C. Morin Hydrate Sensitizes Hepatoma Cells and Xenograft Tumor towards Cisplatin by Downregulating PARP-1-HMGB1 Mediated Autophagy. Int. J. Mol. Sci. 2020, 21, 8253. [Google Scholar] [CrossRef] [PubMed]
  166. Singh, M.P.; Cho, H.J.; Kim, J.T.; Baek, K.E.; Lee, H.G.; Kang, S.C. Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma. Cancers 2019, 11, 986. [Google Scholar] [CrossRef] [PubMed][Green Version]
  167. de Jonge, M.J.; Verweij, J. Renal toxicities of chemotherapy. Semin. Oncol. 2006, 33, 68–73. [Google Scholar] [CrossRef] [PubMed]
  168. Mehta, R.L.; Kellum, J.A.; Shah, S.V.; Molitoris, B.A.; Ronco, C.; Warnock, D.G.; Levin, A.; Acute Kidney Injury, N. Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit. Care 2007, 11, R31. [Google Scholar] [CrossRef] [PubMed][Green Version]
  169. Takahashi, A.; Kimura, T.; Takabatake, Y.; Namba, T.; Kaimori, J.; Kitamura, H.; Matsui, I.; Niimura, F.; Matsusaka, T.; Fujita, N.; et al. Autophagy guards against cisplatin-induced acute kidney injury. Am. J. Pathol. 2012, 180, 517–525. [Google Scholar] [CrossRef] [PubMed]
  170. Kimura, T.; Takabatake, Y.; Takahashi, A.; Kaimori, J.Y.; Matsui, I.; Namba, T.; Kitamura, H.; Niimura, F.; Matsusaka, T.; Soga, T.; et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. JASN 2011, 22, 902–913. [Google Scholar] [CrossRef]
  171. Zhang, D.; Pan, J.; Xiang, X.; Liu, Y.; Dong, G.; Livingston, M.J.; Chen, J.K.; Yin, X.M.; Dong, Z. Protein Kinase Cdelta Suppresses Autophagy to Induce Kidney Cell Apoptosis in Cisplatin Nephrotoxicity. J. Am. Soc. Nephrol. JASN 2017, 28, 1131–1144. [Google Scholar] [CrossRef][Green Version]
  172. Lee, D.; Kang, K.B.; Kim, H.W.; Park, J.S.; Hwang, G.S.; Kang, K.S.; Choi, S.; Yamabe, N.; Kim, K.H. Unique Triterpenoid of Jujube Root Protects Cisplatin-induced Damage in Kidney Epithelial LLC-PK1 Cells via Autophagy Regulation. Nutrients 2020, 12, 677. [Google Scholar] [CrossRef] [PubMed][Green Version]
  173. Wu, J.; Zheng, C.; Wan, X.; Shi, M.; McMillan, K.; Maique, J.; Cao, C. Retinoic Acid Alleviates Cisplatin-Induced Acute Kidney Injury Through Activation of Autophagy. Front. Pharmacol. 2020, 11, 987. [Google Scholar] [CrossRef] [PubMed]
  174. Wang, Y.; Liu, Z.; Shu, S.; Cai, J.; Tang, C.; Dong, Z. AMPK/mTOR Signaling in Autophagy Regulation During Cisplatin-Induced Acute Kidney Injury. Front. Physiol. 2020, 11, 619730. [Google Scholar] [CrossRef] [PubMed]
  175. Minocha, E.; Sinha, R.A.; Jain, M.; Chaturvedi, C.P.; Nityanand, S. Amniotic fluid stem cells ameliorate cisplatin-induced acute renal failure through induction of autophagy and inhibition of apoptosis. Stem Cell Res. Ther. 2019, 10, 370. [Google Scholar] [CrossRef] [PubMed]
  176. Yu, D.; Gu, J.; Chen, Y.; Kang, W.; Wang, X.; Wu, H. Current Strategies to Combat Cisplatin-Induced Ototoxicity. Front. Pharmacol. 2020, 11, 999. [Google Scholar] [CrossRef] [PubMed]
  177. El Nashar, E.M.; Alghamdi, M.A.; Alasmari, W.A.; Hussein, M.M.A.; Hamza, E.; Taha, R.I.; Ahmed, M.M.; Al-Khater, K.M.; Abdelfattah-Hassan, A. Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-beta1/Smad and PI3K/AKT Signaling Pathways. Cells 2021, 10, 2475. [Google Scholar] [CrossRef]
  178. Liang, X.H.; Jackson, S.; Seaman, M.; Brown, K.; Kempkes, B.; Hibshoosh, H.; Levine, B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999, 402, 672–676. [Google Scholar] [CrossRef] [PubMed]
  179. Qu, X.; Yu, J.; Bhagat, G.; Furuya, N.; Hibshoosh, H.; Troxel, A.; Rosen, J.; Eskelinen, E.L.; Mizushima, N.; Ohsumi, Y.; et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Investig. 2003, 112, 1809–1820. [Google Scholar] [CrossRef] [PubMed][Green Version]
  180. Li, Y.; Hahn, T.; Garrison, K.; Cui, Z.H.; Thorburn, A.; Thorburn, J.; Hu, H.M.; Akporiaye, E.T. The vitamin E analogue alpha-TEA stimulates tumor autophagy and enhances antigen cross-presentation. Cancer Res. 2012, 72, 3535–3545. [Google Scholar] [CrossRef] [PubMed][Green Version]
  181. Santanam, U.; Banach-Petrosky, W.; Abate-Shen, C.; Shen, M.M.; White, E.; DiPaola, R.S. Atg7 cooperates with Pten loss to drive prostate cancer tumor growth. Genes Dev. 2016, 30, 399–407. [Google Scholar] [CrossRef][Green Version]
  182. Levy, J.; Cacheux, W.; Bara, M.A.; L’Hermitte, A.; Lepage, P.; Fraudeau, M.; Trentesaux, C.; Lemarchand, J.; Durand, A.; Crain, A.M.; et al. Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth. Nat. Cell Biol. 2015, 17, 1062–1073. [Google Scholar] [CrossRef]
  183. Michaud, M.; Martins, I.; Sukkurwala, A.Q.; Adjemian, S.; Ma, Y.; Pellegatti, P.; Shen, S.; Kepp, O.; Scoazec, M.; Mignot, G.; et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011, 334, 1573–1577. [Google Scholar] [CrossRef]
  184. Ko, A.; Kanehisa, A.; Martins, I.; Senovilla, L.; Chargari, C.; Dugue, D.; Marino, G.; Kepp, O.; Michaud, M.; Perfettini, J.L.; et al. Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling. Cell Death Differ. 2014, 21, 92–99. [Google Scholar] [CrossRef]
  185. Solari, J.I.G.; Filippi-Chiela, E.; Pilar, E.S.; Nunes, V.; Gonzalez, E.A.; Figueiro, F.; Andrade, C.F.; Klamt, F. Damage-associated molecular patterns (DAMPs) related to immunogenic cell death are differentially triggered by clinically relevant chemotherapeutics in lung adenocarcinoma cells. BMC Cancer 2020, 20, 474. [Google Scholar] [CrossRef] [PubMed]
  186. Wahba, J.; Natoli, M.; Whilding, L.M.; Parente-Pereira, A.C.; Jung, Y.; Zona, S.; Lam, E.W.; Smith, J.R.; Maher, J.; Ghaem-Maghami, S. Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer. Cancer Immunol. Immunother. CII 2018, 67, 1753–1765. [Google Scholar] [CrossRef] [PubMed][Green Version]
  187. Heckmann, B.L.; Green, D.R. LC3-associated phagocytosis at a glance. J. Cell Sci. 2019, 132, jcs222984. [Google Scholar] [CrossRef] [PubMed][Green Version]
  188. Cunha, L.D.; Yang, M.; Carter, R.; Guy, C.; Harris, L.; Crawford, J.C.; Quarato, G.; Boada-Romero, E.; Kalkavan, H.; Johnson, M.D.L.; et al. LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance. Cell 2018, 175, 429–441 e416. [Google Scholar] [CrossRef][Green Version]
Figure 1. Primary mechanisms of cisplatin resistance. (a) Decrease in DNA adduct levels. Inward transport: copper transporter 1 (CTR1) and organic cation transporters (OCTs). Outward transport: ATP-binding cassette (ABC) multidrug transporters (including the multidrug resistance proteins and multidrug resistance-associated protein families). ATP7A/B, which belongs to the copper-transporting P-type ATPase, is the response for delivering copper into the organelles and removing the excess copper out of cells. (b) DNA damage recognition defects and increased DNA damage tolerance. (c) Inhibition of apoptosis. (d) Induction of cytoprotective autophagy. APE1: apurinic/apyrimidinic endonuclease 1; ATM: ataxia telangiectasia mutated protein; ATR: ataxia telangiectasia and RAD3-related protein; AMBRA1: activating molecule in Beclin1-regulated autophagy.
Figure 1. Primary mechanisms of cisplatin resistance. (a) Decrease in DNA adduct levels. Inward transport: copper transporter 1 (CTR1) and organic cation transporters (OCTs). Outward transport: ATP-binding cassette (ABC) multidrug transporters (including the multidrug resistance proteins and multidrug resistance-associated protein families). ATP7A/B, which belongs to the copper-transporting P-type ATPase, is the response for delivering copper into the organelles and removing the excess copper out of cells. (b) DNA damage recognition defects and increased DNA damage tolerance. (c) Inhibition of apoptosis. (d) Induction of cytoprotective autophagy. APE1: apurinic/apyrimidinic endonuclease 1; ATM: ataxia telangiectasia mutated protein; ATR: ataxia telangiectasia and RAD3-related protein; AMBRA1: activating molecule in Beclin1-regulated autophagy.
Biomolecules 12 00463 g001
Table 1. Effect of CQ or HCQ on cisplatin-treated cancer cells.
Table 1. Effect of CQ or HCQ on cisplatin-treated cancer cells.
Cancer TypesIn Vitro Study ModelsIn Vivo Study ModelsEffect of CQ or HCQ on Cisplatin SensitivityReference
NSCLCA549/cisplatin cells-Increased[146]
H460 cells-No effect[50]
Endometrial cancer cellsIshikawa/cisplatin cells-Increased[147]
Urothelial carcinoma cellsRT-112/cisplatin cells-Increased[148]
Ovarian cancerA2780-CP20/cisplatin cellsAn orthotopic mouse model established with A2780-CP20 cells and a drug-resistant patient-derived xenograft modelIncreased[149]
ARHI-low expressed SKOV3 cells-No effect[77]
Esophageal cancersEC109/cisplatin cellsNude mice xenografted with EC109/cisplatin cellsIncreased[29]
Neuroblastoma cellsCisplatin-resistant model SK-N-BE(2)Cres cells-Increased[150]
Oral squamous cell carcinomaSCC-4 cells and SCC-4/cisplatin cells-Increased in SCC-4 cells, no effect in SCC-4/cisplatin cells[152]
Pediatric medulloblastoma cellsDAOY and ONS76 cells-no effect[153]
Breast cancer cells67NR and 4T1 cells-no effect[100]
Table 2. Role of autophagy in synergistic effects of natural products and cisplatin.
Table 2. Role of autophagy in synergistic effects of natural products and cisplatin.
CompoundIn Vitro Study ModelsIn Vivo Study ModelsThe Role of Autophagy in Cisplatin Only-Treated ModelsEffect of Combination Treatment on AutophagyReference
Astragaloside IV (AS-IV) derived from Astragalus membranaceusCisplatin-resistant NSCLC cell lines-UnknownDecreased autophagy levels[157]
Hederagenin, a triterpenoid derived from Hedera helixNSCLC cell lines NCI-H1299 and NCI-H1975NCI-H1299 cells xenograft modelUnknownDecreased autophagy levels[161]
Acetyl-11-keto-β-boswellic acid (AKBA), a pentacyclic triterpenes, from Boswellia serrataNSCLC cell lines A549-UnknownDecreased autophagy levels[162]
Andrographolide (Andro), one of the major active components in Andrographis paniculataCisplatin-resistant A549 cellsA549/cisplatin cells xenograft modelUnknownDecreased autophagy levels[163]
Colon cancer cells HCT-116 (p53 wild type and p53-null)-Cytoprotective autophagy (both cell lines)Decreased autophagy levels[164]
Morin hydrate, a bioflavonoid, isolated from the Moraceae familyHepG2 cellHepG2 xenograft nude miceUnknownDecreased autophagy levels[165]
Cisplatin-resistant HepG2 cellsCisplatin-resistant HepG2 xenograft nude miceUnknownDecreased autophagy levels[166]
Gardenia jasminoides (GJ) is a medicinal herb abundant with flavonoidsGlioblastoma multiform U87MG and U373MG cells-Unknown, but induced cytotoxic autophagy when combined with GJIncreased cytotoxic autophagy levels[158]
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Xu, J.; Gewirtz, D.A. Is Autophagy Always a Barrier to Cisplatin Therapy? Biomolecules 2022, 12, 463. https://doi.org/10.3390/biom12030463

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Xu, Jingwen, and David A. Gewirtz. 2022. "Is Autophagy Always a Barrier to Cisplatin Therapy?" Biomolecules 12, no. 3: 463. https://doi.org/10.3390/biom12030463

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