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Cancer Chemotherapy and Chemiluminescence Detection of Reactive Oxygen Species in Human Semen

Antioxidants 2019, 8(10), 471; https://doi.org/10.3390/antiox8100471

Review
Redox-Mediated Mechanism of Chemoresistance in Cancer Cells
1
Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Korea
2
Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
*
Author to whom correspondence should be addressed.
Received: 18 September 2019 / Accepted: 8 October 2019 / Published: 10 October 2019

Abstract

:
Cellular reactive oxygen species (ROS) status is stabilized by a balance of ROS generation and elimination called redox homeostasis. ROS is increased by activation of endoplasmic reticulum stress, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family members and adenosine triphosphate (ATP) synthesis of mitochondria. Increased ROS is detoxified by superoxide dismutase, catalase, and peroxiredoxins. ROS has a role as a secondary messenger in signal transduction. Cancer cells induce fluctuations of redox homeostasis by variation of ROS regulated machinery, leading to increased tumorigenesis and chemoresistance. Redox-mediated mechanisms of chemoresistance include endoplasmic reticulum stress-mediated autophagy, increased cell cycle progression, and increased conversion to metastasis or cancer stem-like cells. This review discusses changes of the redox state in tumorigenesis and redox-mediated mechanisms involved in tolerance to chemotherapeutic drugs in cancer.
Keywords:
reactive oxygen species; antioxidant proteins; chemoresistance; oxaliplatin; 5-Fluorouracil

1. Introduction

Reactive oxygen species (ROS), as second messengers, function in various cellular signal pathways in normal cells and cancer cells [1]. Redox homeostasis is regulated by a balanced status between ROS production and scavenging (Figure 1) [1,2]. Signal cascades induced by stimuli can lead to ROS generation from ligand-receptor interactions [2,3,4]. Molecules that can directly penetrate the cell membrane, such as lipophilic growth hormones (steroid hormones and thyroid hormones) and chemical drugs, can activate mitochondrial-mediated ROS generation [5,6,7]. Although various stimuli can induce changes in ROS and affect the physiological response in cells, the antioxidant proteins stabilize ROS levels to maintain redox homeostasis [8]. Superoxide dismutase (SOD), catalase, peroxiredoxin (Prx), and nuclear factor erythroid 2-related factor 2 (Nrf2) are antioxidant modules [9]. Local ROS level, as a second messenger, amplifies only the specific region where receptor activation transduces a linear signal response. [3,10]. This process is regulated locally by ROS inducers and antioxidant modules to overcome the possibility that the alternative ROS can affect whole cells [3].
Many studies have shown that redox imbalances can induce signaling pathways that promote cancer progression, senescence, differentiation, and apoptosis [8]. Cancer cells show enhanced glycolysis-mediated metabolisms to overcome over-utilized ATP or alter cellular signal pathways [11]. Thus, many cancer cells upregulate antioxidants as protection against their high levels of ROS. Chemotherapeutic agents can induce increased ROS levels, and most cancer cells treated with chemotherapy suffer from ROS-mediated apoptosis [12]. Some cancer cells evolve mechanisms to escape ROS-mediated apoptosis and acquire tolerance to anti-cancer drugs [13]. The ROS system has a dual function that can either induce apoptosis or allow cells to adapt to various environments. ROS regulation has thus been a critical target for the development of anticancer drugs [14]. In this review, we discuss the change of redox balance by the generation or removal of ROS in tumorigenesis and redox-mediated mechanisms of the chemoresistance in chemotherapy.

2. Redox Homeostasis in Tumorigenesis

2.1. ROS Generation

Intracellular redox functions as an oncogenic factor for the activation of signal transduction in tumorigenesis [9]. ROS consists of both free radical and non-radical groups. The free radical group includes superoxide anion (O2), peroxyl radical (RO2•), hydroxyl radical (•OH), and hydroperoxyl radical (HO2•). Hydrogen peroxide (H2O2) and single oxygen (1O2) are classified as non-radical ROS. Production of intracellular ROS is generated by ATP synthesis in mitochondria, protein synthesis in the endoplasmic reticulum (ER), and activation of (NADPH) oxidase NOX family members [5].

2.1.1. ATP Synthesis in Mitochondria

Mitochondria generate intracellular ROS during the electron transport chain (ETC) of the ATP synthesis process [15]. The homeostasis of ROS in mitochondria is maintained by antioxidant proteins. Upon electron leakage of the ETC, the abnormal ROS status of mitochondria can activate apoptosis in carcinoma cells [15,16].
Cancer cells show increased metabolism for their elevated proliferation and migration. Cancer cells have significantly increased the ATP production as well as the ROS [15,16,17,18]. Chemoresistant cancer cells require the active pump of the ATP-driven multidrug efflux, such as ATP-binding cassette (ABC) transporters [19]. The role of these transporters is to pump out intracellular toxic chemical drugs into the extracellular region by ATP hydrolysis [20]. ABC transporters include multidrug resistance-associated protein 1 (MRP1/ABCC1), breast cancer resistance protein/ABC subfamily G member 2 (BCRP/ABCG2), ABC subfamily B member 5 (ABCB5), and multidrug resistance protein 1/ABC subfamily B member 1 (MDR1/ABCB1) [19,20,21]. Enhanced ROS level is generated by the ETC, but the antioxidant machinery is also induced to adapt to the higher ROS level. Thus, regulation of the ETC in mitochondria may be a good approach to overcome chemoresistance via the blockage of routes that generate ATP or the dysregulation of ROS production that induces apoptosis.

2.1.2. Endoplasmic Reticulum (ER)

The ER is a dynamical cellular organelle that plays a role the protein folding system, which regulates almost all of the membrane proteins and secretory proteins for post-translational modification [22,23]. The intracellular H2O2 in the process of protein synthesis in ER is generated by the formation of disulfide bridges during the induction of functional three-dimensional structures via protein disulfide isomerase (PDI) and other oxidoreductases [24,25]. Thus, the intracellular ROS status of ER maintains the relatively high level [26,27]. The ER-stress induced response is involved in the survival, metastasis, and angiogenesis in cancer cells under rough microenvironmental situations [28,29].

2.1.3. NADPH Oxidases (NOXs)

The NOX family members consist of NOX1–5 and dual oxidase (DUOX) 1 and 2 [30]. H2O2 and O2•− produced by NOXs function as secondary messengers to transduce signals in response to various growth-related factors and chemical drugs [31,32,33]. NOX-induced ROS production provokes the acquisition of chemoresistance and contributes to cancer progression [34,35].
NOX1 is mainly located at the plasma membrane and endosome. NOX2 and NOX5 are located in the ER and plasma membrane [36,37]. NOX3 is localized mostly at the plasma membrane as well as mitochondria. NOX4 is also localized at the plasma membrane, the ER, the inner membrane of mitochondria and nucleus [38]. DUOX1 is located in the plasma membrane and ER, while DUOX2 is localized to the plasma membrane, ER, and cytosol as well as mitochondria and nucleus [30].
NOX1 and NOX5 regulate the drug efficacy of chemotherapy in prostate cancer [39]. NOX2 expression is related to invasion and progression in gastric cancer and acute myeloid leukemia (AML) [40,41]. NOX4 has a function of regulation in drug resistance [34]. Overexpression of DUOX and NOX4 has been detected in human thyroid tumors [35]. Due to the limits of expression in the inner ear epithelial cells and cochlea, the precise role of NOX3 in cancer is unknown [30,42]. In pancreatic ductal carcinoma, the elevated ROS level by activated NOXs induces tolerance against chemotherapy and radiation therapy [43,44,45]. The target of NOXs is a druggable strategy to treat cancer by drugs that inhibit NOXs, and cancer cells can be treated by inducing redox state-mediated triggers of apoptosis [46].

2.2. ROS Elimination

Redox homeostasis is regulated by the antioxidant enzymes. Cancer cells maintain sustained overexpression of antioxidant proteins to detoxify the ROS byproducts of over-activated cellular metabolisms.

2.2.1. SODs

SOD is an enzyme that catalyzes the partitioning of two superoxide anions into hydrogen peroxide and molecular oxygen by the metalloenzymatic reaction [47]. SOD dependent-neutralization is important as the cell’s first barricade to ROS in the antioxidant systems. SOD has specific metal cofactors for the enzymatic activity such as SOD1 with copper (Cu) and zinc (Zn), SOD2 with manganese (Mn), and SOD3 with copper (Cu) and zinc (Zn) [48]. The SOD family is consisted of SOD1 (Cu/ZnSOD), SOD2 (MnSOD), and SOD3 (Cu/ZnSOD) [47,48]. The expression of SOD1, the most abundant SOD protein in cytoplasm, is increased in mammary carcinomas and lung carcinomas [48,49]. SOD2 was identified as downregulated in tumors in early studies, and thus SOD2 was initially considered a tumor suppressor [50]. However, recent studies have shown that SOD2 exhibits tumor-type dependent function [51,52]. SOD2 levels are higher in late-stage tumors as well as in invasive and metastatic cancers [48,50,53]. SOD2 also functions in the regulation of mitochondrial integrity and function [51,53]. Thus, SOD2 plays an important role in tumor progression. SOD3, or extracellular superoxide dismutase EcSOD, is localized in the extracellular matrix and binds to the glycocalyx in cell surfaces [54]. SOD3 functions neutralize from O2 by the membrane-bound NOXs to H2O2 [54,55,56]. The role of SOD3 in cancer is less known.

2.2.2. Catalase

Catalase is a 62 kDa enzyme and consists of four identical subunits, including an N-terminal region for catalase reaction, a beta-barrel region for three-dimensional structure, a connection region for binding heme groups, and an alpha-helix region for NADPH binding [57,58]. The major function of catalase is to metabolize high concentrations of H2O2 for the protection of ROS-induced damage in cells. The reaction mechanism of catalase occurs in two-steps using heme groups. The first reaction is a process in which the heme cofactor reacts with a single molecule of H2O2 to produce an oxidative heme group (an oxoferryl porphyrin cation radical, which reduces the return to the previous step). In the second reaction, the oxoferryl porphyrin cation radical of catalase rapidly reacts with the second molecule of H2O2 to produce oxygen byproducts and water [58].
Another role of catalase is in the regulation of the integrin pathway during proliferation or migration [58]. Overexpression of catalase has been detected in various carcinomas, such as chronic myeloid leukemia, gastric cancer, and skin cancer [59,60,61]. Anticancer drugs also increased catalase levels in oral cancer cells, bladder cancer cells, pancreatic cancer cells, and gastric cancer cells [62,63,64,65]. Catalase expression is controlled by various mechanisms. At the transcriptional level, the expression of catalase is regulated by the activity of transcription factors on the catalase promoters, mRNA stability, and epigenetic chromatin structure [57,58]. At the protein level, the expression of catalase is affected by post-translational modification such as ubiquitination and phosphorylation [57,58].

2.2.3. Prxs

Prx is a thiol-specific peroxidase protein without other cofactors for detoxification of H2O2 to H2O. The reaction mechanism by which Prx decomposes H2O2 into H2O occurs through a cycle, where peroxidatic Cys (CP-SH) of Prx reacts with H2O2 to oxidize to sulfenic acid (CP-SOH) and then back to a reduced peroxidatic Cys (CP-SH) state with the presence of reducing equivalents [66]. Prxs maintain cellular ROS homeostasis through this catalytic cycle [66,67]. The Prx family includes Prx1 to Prx6. Prx1 and Prx2 are located in the cytosol and nucleus, and Prx3 is localized in mitochondria. Prx4 is localized to the ER, the cytosol, and secretion. Prx5 is located in the cytosol, nucleus, mitochondria, and peroxisomes [66,68]. Prx6 is located in the nucleus, cytosol, extracellular space, and lysosome [69]. Most Prx family members are overexpressed in various carcinomas and may serve as biomarkers for cancer diagnosis [70]. Prx1 functions as an oncogenic factor in tumorigenesis. Prx1 leads to reduced DNA damage and apoptosis by detoxifying ROS. Prx1 also regulates cell signaling including NF-κB, JNK, Akt, p38 activity, VEGF, and ERK pathways [66]. Therefore, overexpression of Prx1 causes aberrant cell signaling that is beneficial for cancer cells. Prx2 function is paradoxical; Prx2 not only induces activation of the ERK pathway for promotion of metastasis but also stabilizes E-cadherin for suppression of metastasis [71,72]. Prx3 is an oncogenic factor and induces carcinogenesis via tolerance to ROS [66]. Prx4, Prx5, and Prx6 promote metastasis via clearance of increased ROS level in cancers [68,69,70].

2.2.4. Nrf2

Nrf2 is a transcription factor containing the basic-region leucine zipper domain. Nrf2 is maintained at low levels by Keap1-mediated ubiquitin-dependent proteasomal degradation in the normal condition of cells [73]. Under oxidative stress or exposure to different stressors, Nrf2 is released form Keap1 due to the modification of the Keap1 Cys residue, which prevents ubiquitin-dependent proteasomal degradation of Nrf2 [73]. Nrf2 plays a role in protecting cells from oxidative stress-mediated damages through expression of target genes involved in detoxification. Nrf2-dependent gene families include antioxidant genes (SOD, CAT, Prx, GR, and TR) and genes involved in drug metabolism/transport (MRP1 and BCRP/ABCG2) (Figure 2) [74,75,76]. MRP belong to a family of membrane-anchored transporters and pump out a wide range of compounds, including peptides, lipids, organic anions, and drugs through ATP hydrolysis [76]. Carcinogenesis or chemoresistance in various cancers such as breast cancer, leukemia, neuroblastoma, and lung cancer increases the expression of Nrf2 or induces hyper-activation [77,78,79,80]. Therefore, a combination of Nrf2 inhibitors with anticancer drugs may derive therapeutic effects in patients [76].

2.3. Redox Homeostasis of Chemoresistance

Chemoresistance arises after long-time exposures to anticancer drugs [81,82]. The difference between temporary treatment and continuous treatment leads to different levels of ROS homeostasis in cancer cells. Cancer cells regulate ROS levels to acquire chemoresistance [13].

2.3.1. Oxaliplatin Resistance

Oxaliplatin is a platinum-based drug that is widely used in lung cancer, breast cancer, pancreatic cancer, and gastric cancer [6]. The cytotoxicity mechanism of oxaliplatin involves its binding genomic DNA, which induces apoptosis in cancer cells, and the generation of ribosome biogenesis stress [6,83].
Resistance to oxaliplatin decreases the production of ROS levels [83,84,85]. However, alterations of NAPDH oxidase, ER stress, and ETC in mitochondria in oxaliplatin-resistant cells have not been deeply investigated. Oxaliplatin can also form mitochondrial DNA adducts and affect protein synthesis in mitochondria, resulting in mitochondrial abnormalities [86]. Treatment of oxaliplatin induces dysfunction in the mitochondrial respiratory chain and permeability [86,87]. High concentrations of oxaliplatin enhance ROS levels in mitochondria [86,87].
Oxaliplatin-resistant cell lines show altered expression of antioxidant proteins. Upregulated SOD1 and SOD2 detoxify drug-mediated radical species in oxaliplatin-resistant colon cancer cells [88]. SOD3 is also highly expressed in the mouse model of oxaliplatin-induced liver injury [89]. Oxaliplatin-resistant colon cancer cells have increased Nrf2 expression and exhibit chemotherapeutic effects via inhibition of Nrf2 signaling [90,91].

2.3.2. 5-Fluorouracil (5-FU) Resistance

5-FU is an uracil analog drug that is widely used in various cancers. 5-FU induces DNA and RNA damage in the nucleus and mitochondria from byproducts of cellular 5-FU metabolism [92].
5-FU resistance causes a high level of intracellular ROS in colon cancer cells [93,94,95]. DUOX2 expression is altered in response to 5-FU resistance. The expression of DUOX2 is enhanced in 5-FU chemoresistant colon cancer cell lines. The upregulation of DUOX2 induces high levels of ROS and invasion ability [96]. ER-stress related factors, including PERK, GRP78, and ATF6, are upregulated in 5-FU tolerant colon cancer cells [97].
5-FU incorporation into mitochondrial DNA induces destabilization of mitochondrial DNA and protein synthesis. 5-FU can also induce ROS-mediated damage in mitochondria [98,99]. 5-FU resistance leads to a down-regulation of ATP synthesis via lower expression of ATP synthase subunits or reduced activity of ATP synthase [100,101]. Drug resistance to 5-FU induces a high level of SOD1 and Prx1 in the adaption of increased intracellular ROS conditions [102,103]. In several cancer cells, the expression or intracellular location of Nrf2 is associated with 5-FU resistance [95,103,104,105,106,107]. For example, Nrf2 is overexpressed in 5-FU resistant gastric cancer and nuclear localization, and the expression of Nrf2 is increased in 5-FU resistant colorectal cancer cells [95,105,106,107].

3. Redox-Mediated Mechanism of Chemoresistance

Multidrug resistance (MDR) is regulated by the upregulation of antioxidant proteins (hemooxygenase-1, superoxide dismutase, catalase). These antioxidant factors detoxify the altered intracellular ROS levels. Variation of the ROS level is required for chemoresistance or for the upregulation of drug efflux against chemotherapy [13,102]. ROS-mediated mechanisms for acquired chemoresistance involve ER stress and autophagy, cell cycle perturbation for overcoming cell cycle arrest, and reprogramming for promoting epithelial to mesenchymal transition or conversion to cancer stem-like cells (Figure 3) [31,104,108,109,110,111,112].

3.1. ER Stress-Mediated Autophagy

ROS play an important role in switching from ER stress-mediated apoptosis to autophagy in drug-resistant carcinomas [110]. Acquired resistance to anti-cancer drugs in cancer cells also results in tolerance to ER stress-mediated cell death [113]. The ER stress response also serves as a survival signal for chemoresistance in cancers [114,115]. The ER stress response is controlled by inositol-requiring enzyme-1 (IRE1), protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) in normal cells [116,117]. The loss of tumor suppressor factors or activation of oncogenes often induces activation of ER stress response-related factors to generate tumorigenesis in response to chemotherapy [97,118]. PERK is associated with the upregulation of the MDR-related protein MRP1 in chemoresistant colon adenocarcinoma cell lines [119].
Autophagy is a highly controlled degradation system of damaged organelles and protein aggregation. Autophagy is activated by starvation, organelle damage, and ER stress, and various cancers show dysfunction in autophagy [120,121]. ROS is another stimulus that can activate autophagy. H2O2 accumulation can result in oxidization of ATG4, a factor involved in the autophagic process [122,123,124]. Oxidation of ATG4 induces initiation of autophagy [125,126].

3.1.1. Oxaliplatin-Resistance

Regulation of autophagy is one of the mechanisms of oxaliplatin resistance. The tolerance of colon cancer cell lines to oxaliplatin involves the down-regulation of Bcl2-modifying factor (BMF), ATG7, and Beclin-1 [127]. BMF induces necrosis, apoptosis, and autophagy [128,129,130]. Chemoresistance can be acquired by activated autophagy depending on the cell type. Oxaliplatin-resistant hepatocellular carcinoma shows autophagy activation via ROS generation and induced modulation of autophagosomes, LC3-II accumulation, and LC3 redistribution [86,131].

3.1.2. 5-FU-Resistance

Chemoresistance to 5-FU is regulated by autophagy systems, although autophagy is increased or decreased in various cancers. Autophagy-related proteins, including Beclin-1, ATG5, and LC3-II, are downregulated in 5-FU-resistant human colon cancer cells [94]. However, 5-FU-resistant breast cancer cell lines show overexpression of ATG5, Beclin-1, LC3-II, and increased autophagy [132].

3.2. Overcoming Cell Cycle Arrest

Aberrant levels of ROS result in increased cell cycle progression to bypass arrest and acquire chemoresistance against cancer chemotherapies [108,112]. The cell cycle is regulated by positive regulators, cyclin and cyclin-dependent kinases (CDKs), and negative factors, including cyclin-dependent kinase inhibitors [108,133]. One of the hallmarks of the early stage of cancer is abnormal cell cycle progression resulting from the dysregulation of cell cycle-related factors [82,108,134].
The cell cycle progression is responsive to changes in the redox state of metabolism [112]. The redox signaling pathways alters cell cycle progression that converges as a regulator of CDK [135]. Altered ROS levels promote increased cell cycle via phosphorylation of cell cycle regulatory factors or upregulation of the cyclin family [136,137,138,139]. Cyclin D1 is overexpressed in various human carcinomas [140,141,142]. Overproduction of ROS leads to metastasis via regulation of cyclin D1, which functions in the invasion and metastatic properties of tumors [143,144].

3.2.1. Oxaliplatin-Resistance

Acquired oxaliplatin resistance affects cell cycle progression. The oxaliplatin-resistant LoVo cell line has overcome oxaliplatin-mediated G2 phase arrest [145]. Overexpression of the cell cycle 5regulators cyclin D1 and B1 are reported in the oxaliplatin-resistant HT-29 cell line [146].

3.2.2. 5-FU-Resistance

5-FU affects cell cycle perturbation by its incorporation in DNA and interfering with DNA synthesis [100]. Cancer cells with treatment of 5-FU have sufficient time during the cell cycle to correct the mis-incorporated fluoronucleotides and prolong DNA synthesis during the cell cycle [100,147]. However, cell lines with acquired chemoresistance show high expressions of cell cycle-related activators that result in resistance to cell cycle arrest. Breast cancer cell lines with 5-FU resistance show upregulation of cell cycle-related proteins and enhanced cellular proliferation [148,149]. 5-FU resistance results in modified expression of G1 phase cyclins in oral cancer cell lines and aberrant cell cycle regulation [100,150].

3.3. Epithelial-Mesenchymal Transition (EMT) and Cancer Stem-Like Cells (CSC)

The EMT process allows metastatic tumor cells to migrate to organs. Altered intracellular ROS levels may lead to the promotion of EMT in cancer cell lines that are resistant to anti-cancer drugs [81,108]. Several proteins function in the development of chemoresistance in metastatic advanced carcinomas [151,152]. Chemoresisance in cancer cells results in switching from chemotherapy-mediated apoptosis to EMT properties. Moreover, EMT-related signaling pathways, such as sonic hedgehog (SHH), Notch, TGF-ꞵ, and Wnt, overlap with renewal and maintenance of CSC [153,154]. Metastatic characterized cancer cells show phenotypes of both EMT and CSC [155,156].
Some chemoresistant cancer cell lines have characteristics of CSCs, including decreased proliferation, a greater proportion of G0/G1 cells, and increased ability of sphere-forming capacity [157,158]. The ABC transporter is related with drug resistance and cancer stem like-cells [159].

3.3.1. Oxaliplatin-Resistance

Resistant to oxaliplatin results in enhanced migration and invasion abilities in colon cancer cells [160,161]. CCN2 and ID-1 are upregulated in oxaliplatin-resistant tumor cells [162,163]. CCN2 regulates cell proliferation, chemotaxis, and migration, while ID-1 is involved in blocking cell differentiation [162,163,164]. The Cx32 tumor suppressor protein is associated with positive expression of E-cadherin and negative expression of vimentin [165,166]. Cx32 level is decreased in hepatocellular carcinoma resistant to oxaliplatin [165]. Ataxin-2-line (ATXN2L) promotes migration and invasion and is elevated in oxaliplatin-resistant gastric cancer [167,168]. The cancer stem-like cell markers Oct4 and Sox2 are increased in oxaliplatin-resistant colon cancer cell lines [169].

3.3.2. 5-FU-Resistance

Acquired 5-FU resistance results in altered EMT-related morphological phenotypes, such as reduced cellular adhesion, down-regulation of E-cadherin, up-regulation of N-cadherin and twist, the enlarged formation of pseudopodia and spindle-shaped morphology [170,171]. 5-FU-resistant carcinoma cell lines show high expression of vimentin, ZEB1, ZEB2, slug, snail, twist, and N-cadherin [170,172,173,174,175]. Low level of E-cadherin has been reported during 5-FU resistance of various cancer cell lines [172,174]. Increased mesenchymal factors enhanced migration. TGF-beta-mediated EMT and cancer stem-like cell capacities are reported in 5-FU-resistant pancreatic cancer cell lines [176]. CD44 is a cell surface marker of cancer stem-like cells. CD44 variant 9 is high in 5-FU-resistant gastric cancer cell lines [177,178]. Some colon cancer cells with 5-FU-resistance show features of cancer stem-like cells [179].

4. Conclusions

ROS are involved in physiological signal cascades in normal and cancer cells. Most of drug or growth factors induce downstream cascades that result in short-lived ROS generation. Antioxidant proteins, as ROS scavengers, play a role in the detoxification of ROS and can regulate the intensity of ROS-mediated signal transduction. Thus, cancer cells regulate the redox homeostasis to survival. ROS-mediated chemoresistance is regulated by the control of ER stress-mediated autophagy, overactivation of cell proliferation, and promotion of EMT and cancer stem-like cells.
The antioxidant system includes diverse proteins such as SOD, catalase, Prx, glutathione peroxidase, and thiol peroxidase, among others. Nrf2 has increased the expression and activity in oxaliplatin or 5-FU resistant cancer cells. Several antioxidant proteins are up-regulated in chemoresistance such as SOD1, SOD2, and SOD3 in oxaliplatin-resistant cancer cells or SOD1 and Prx1 in 5-FU chemoresistance. However, studies of variation in function or expression of other antioxidant proteins in chemoresistance are limited. Investigation of the regulation of antioxidant proteins is required for overcoming chemoresistance by regulation of the redox state, and better understanding of this process may provide new targets for the development of anti-cancer drugs.
The mechanism for acquired chemoresistance may be paradoxical. Regulation of autophagy in chemoresistance results in different responses depending on the cell type. Although chemoresistant cancer cell lines show upregulated proliferation, some chemoresistant cells become cancer stem-like cells, which are characterized by low proliferation. Thus, whether the mechanism of chemoresistance is cell type-specific should be examined in future studies. Due to the characteristic of each cell, this phenomenon (that uses different mechanisms of chemoresistance acquisition in cancer cells) is induced by signal transduction proteins such as Akt, mTOR, ERK, p38, SHH, and Wnt, depending on the activity or expression level of kinases. Most drugs change ROS status in cancers. However, ROS-mediated mechanism can occur by different pathways. Therefore, investigation of chemoresistance can reveal some of kinases with hyperactivation or hypoactivation. These results provide clues to the development of drugs in chemoresistant-related therapies.
In conclusion, clarifying the mechanisms underlying the regulation of redox-mediated chemoresistance may provide targets for drug development for overcoming chemoresistance in preclinical and clinical settings.

Author Contributions

Conceptualization, E.-K.K. and H.H.J.; data curation, M.J.; writing—original draft preparation, E.-K.K., M.-J.S., and H.H.J.; writing—review and editing, E.-K.K., D.K., Y.K., and H.H.J.; visualization, M.J.; supervision, H.H.J.; funding acquisition, M.J., and E.-K.K.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2017R1D1A1B03035550) to E.-K.K., and by the National Research Foundation of Korea (NRF) and the Center for Women In Science, Engineering and Technology (WISET) Grant funded by the Ministry of Science, ICT & Future Planning of Korea (MSIP) under the Program for Returners into R&D to M.J.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ray, P.D.; Huang, B.W.; Tsuji, Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 2012, 24, 981–990. [Google Scholar] [CrossRef] [PubMed]
  2. Lu, Q.B.; Wan, M.Y.; Wang, P.Y.; Zhang, C.X.; Xu, D.Y.; Liao, X.; Sun, H.J. Chicoric acid prevents PDGF-BB-induced VSMC dedifferentiation, proliferation and migration by suppressing ROS/NFkappaB/mTOR/P70S6K signaling cascade. Redox Biol. 2018, 14, 656–668. [Google Scholar] [CrossRef] [PubMed]
  3. Nordzieke, D.E.; Medrano-Fernandez, I. The Plasma Membrane: A Platform for Intra- and Intercellular Redox Signaling. Antioxidants 2018, 7, 168. [Google Scholar] [CrossRef] [PubMed]
  4. Choi, M.H.; Lee, I.K.; Kim, G.W.; Kim, B.U.; Han, Y.H.; Yu, D.Y.; Park, H.S.; Kim, K.Y.; Lee, J.S.; Choi, C.; et al. Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 2005, 435, 347–353. [Google Scholar] [CrossRef] [PubMed]
  5. Dharmaraja, A.T. Role of Reactive Oxygen Species (ROS) in Therapeutics and Drug Resistance in Cancer and Bacteria. J. Med. Chem. 2017, 60, 3221–3240. [Google Scholar] [CrossRef] [PubMed]
  6. Martinez-Balibrea, E.; Martinez-Cardus, A.; Gines, A.; Ruiz de Porras, V.; Moutinho, C.; Layos, L.; Manzano, J.L.; Bugés, C.; Bystrup, S.; Esteller, M.; et al. Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance. Mol. Cancer Ther. 2015, 14, 1767–1776. [Google Scholar] [CrossRef]
  7. Nobel, S.; Abrahmsen, L.; Oppermann, U. Metabolic conversion as a pre-receptor control mechanism for lipophilic hormones. Eur. J. Biochem. 2001, 268, 4113–4125. [Google Scholar] [CrossRef]
  8. Moloney, J.N.; Cotter, T.G. ROS signalling in the biology of cancer. Semin. Cell Dev. Biol. 2018, 80, 50–64. [Google Scholar] [CrossRef]
  9. Yang, H.; Villani, R.M.; Wang, H.; Simpson, M.J.; Roberts, M.S.; Tang, M.; Liang, X. The role of cellular reactive oxygen species in cancer chemotherapy. J. Exp. Clin. Cancer Res. 2018, 37, 266. [Google Scholar] [CrossRef]
  10. Sauer, H.; Wartenberg, M.; Hescheler, J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell. Physiol. Biochem. 2001, 11, 173–186. [Google Scholar] [CrossRef]
  11. Gorrini, C.; Harris, I.S.; Mak, T.W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 2013, 12, 931–947. [Google Scholar] [CrossRef]
  12. Galadari, S.; Rahman, A.; Pallichankandy, S.; Thayyullathil, F. Reactive oxygen species and cancer paradox: To promote or to suppress? Free Radic. Biol. Med. 2017, 104, 144–164. [Google Scholar] [CrossRef]
  13. Cui, Q.; Wang, J.Q.; Assaraf, Y.G.; Ren, L.; Gupta, P.; Wei, L.; Ashby, C.R., Jr.; Yang, D.-H.; Chen, Z.-S. Modulating ROS to overcome multidrug resistance in cancer. Drug Resist. Updat. 2018, 41, 1–25. [Google Scholar] [CrossRef]
  14. Zou, Z.; Chang, H.; Li, H.; Wang, S. Induction of reactive oxygen species: An emerging approach for cancer therapy. Apoptosis 2017, 22, 1321–1335. [Google Scholar] [CrossRef]
  15. Porporato, P.E.; Filigheddu, N.; Pedro, J.M.B.; Kroemer, G.; Galluzzi, L. Mitochondrial metabolism and cancer. Cell Res. 2018, 28, 265–280. [Google Scholar] [CrossRef]
  16. Porporato, P.E.; Payen, V.L.; Baselet, B.; Sonveaux, P. Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism. Cell. Mol. Life Sci. 2016, 73, 1349–1363. [Google Scholar] [CrossRef]
  17. Oliva, C.R.; Markert, T.; Ross, L.J.; White, E.L.; Rasmussen, L.; Zhang, W.; Everts, M.; Moellering, D.R.; Bailey, S.M.; Suto, M.J.; et al. Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells. J. Biol. Chem. 2016, 291, 24188–24199. [Google Scholar] [CrossRef]
  18. Cheng, C.W.; Kuo, C.Y.; Fan, C.C.; Fang, W.C.; Jiang, S.S.; Lo, Y.K.; Kao, M.C.; Lee, A.Y.L. Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species. Cell Death Dis. 2013, 4, e681. [Google Scholar] [CrossRef]
  19. Prieto-Vila, M.; Takahashi, R.U.; Usuba, W.; Kohama, I.; Ochiya, T. Drug Resistance Driven by Cancer Stem Cells and Their Niche. Int. J. Mol. Sci. 2017, 18, 2574. [Google Scholar] [CrossRef]
  20. Lobo, N.A.; Shimono, Y.; Qian, D.; Clarke, M.F. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol. 2007, 23, 675–699. [Google Scholar] [CrossRef]
  21. Vasiliou, V.; Vasiliou, K.; Nebert, D.W. Human ATP-binding cassette (ABC) transporter family. Hum. Genom. 2009, 3, 281–290. [Google Scholar] [CrossRef]
  22. Bahar, E.; Kim, J.Y.; Yoon, H. Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling. Cancers 2019, 11, 338. [Google Scholar] [CrossRef]
  23. Zhang, Z.; Zhang, L.; Zhou, L.; Lei, Y.; Zhang, Y.; Huang, C. Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress. Redox Biol. 2018. [Google Scholar] [CrossRef] [PubMed]
  24. Qin, M.; Wang, W.; Thirumalai, D. Protein folding guides disulfide bond formation. Proc. Natl. Acad. Sci. USA 2015, 112, 11241–11246. [Google Scholar] [CrossRef] [PubMed]
  25. Malhotra, J.D.; Kaufman, R.J. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword? Antioxid. Redox Signal. 2007, 9, 2277–2293. [Google Scholar] [CrossRef] [PubMed]
  26. Araki, K.; Iemura, S.; Kamiya, Y.; Ron, D.; Kato, K.; Natsume, T.; Nagata, K. Ero1-alpha and PDIs constitute a hierarchical electron transfer network of endoplasmic reticulum oxidoreductases. J. Cell Biol. 2013, 202, 861–874. [Google Scholar] [CrossRef] [PubMed]
  27. Enyedi, B.; Varnai, P.; Geiszt, M. Redox state of the endoplasmic reticulum is controlled by Ero1L-alpha and intraluminal calcium. Antioxid. Redox Signal. 2010, 13, 721–729. [Google Scholar] [CrossRef] [PubMed]
  28. Cubillos-Ruiz, J.R.; Bettigole, S.E.; Glimcher, L.H. Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer. Cell 2017, 168, 692–706. [Google Scholar] [CrossRef]
  29. Oakes, S.A. Endoplasmic reticulum proteostasis: A key checkpoint in cancer. Am. J. Physiol. Cell Physiol. 2017, 312, C93–C102. [Google Scholar] [CrossRef]
  30. Brandes, R.P.; Weissmann, N.; Schroder, K. Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic. Biol. Med. 2014, 76, 208–226. [Google Scholar] [CrossRef]
  31. Weng, M.S.; Chang, J.H.; Hung, W.Y.; Yang, Y.C.; Chien, M.H. The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance. J. Exp. Clin. Cancer Res. 2018, 37, 61. [Google Scholar] [CrossRef] [PubMed]
  32. Miyata, Y.; Matsuo, T.; Sagara, Y.; Ohba, K.; Ohyama, K.; Sakai, H. A Mini-Review of Reactive Oxygen Species in Urological Cancer: Correlation with NADPH Oxidases, Angiogenesis, and Apoptosis. Int. J. Mol. Sci. 2017, 18, 2214. [Google Scholar] [CrossRef] [PubMed]
  33. Vara, D.; Watt, J.M.; Fortunato, T.M.; Mellor, H.; Burgess, M.; Wicks, K.; Mace, K.; Reeksting, S.; Lubben, A.; Wheeler-Jones, C.P.D.; et al. Direct Activation of NADPH Oxidase 2 by 2-Deoxyribose-1-Phosphate Triggers Nuclear Factor Kappa B-Dependent Angiogenesis. Antioxid. Redox Signal. 2018, 28, 110–130. [Google Scholar] [CrossRef] [PubMed]
  34. Shanmugasundaram, K.; Nayak, B.K.; Friedrichs, W.E.; Kaushik, D.; Rodriguez, R.; Block, K. NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance. Nat. Commun. 2017, 8, 997. [Google Scholar] [CrossRef] [PubMed]
  35. Ameziane-El-Hassani, R.; Schlumberger, M.; Dupuy, C. NADPH oxidases: New actors in thyroid cancer? Nat. Rev. Endocrinol. 2016, 12, 485–494. [Google Scholar] [CrossRef] [PubMed]
  36. Laurindo, F.R.; Araujo, T.L.; Abrahao, T.B. Nox NADPH oxidases and the endoplasmic reticulum. Antioxid. Redox Signal. 2014, 20, 2755–2775. [Google Scholar] [CrossRef]
  37. Fulton, D.J. Nox5 and the regulation of cellular function. Antioxid. Redox Signal. 2009, 11, 2443–2452. [Google Scholar] [CrossRef] [PubMed]
  38. Mason, C.V.; Hines, M.C. Alpha, beta, and gamma crystallins in the ocular lens of rabbits: Preparation and partial characterization. Investig. Ophthalmol. 1966, 5, 601–609. [Google Scholar]
  39. Holl, M.; Koziel, R.; Schafer, G.; Pircher, H.; Pauck, A.; Hermann, M.; Klocker, H.; Jansen-Dürr, P.; Sampson, N. ROS signaling by NADPH oxidase 5 modulates the proliferation and survival of prostate carcinoma cells. Mol. Carcinog. 2016, 55, 27–39. [Google Scholar] [CrossRef]
  40. Marlein, C.R.; Zaitseva, L.; Piddock, R.E.; Robinson, S.D.; Edwards, D.R.; Shafat, M.S.; Zhou, Z.; Lawes, M.; Bowles, K.M.; Rushworth, S.A. NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood 2017, 130, 1649–1660. [Google Scholar] [CrossRef]
  41. Wang, P.; Shi, Q.; Deng, W.H.; Yu, J.; Zuo, T.; Mei, F.C.; Wang, W.X. Relationship between expression of NADPH oxidase 2 and invasion and prognosis of human gastric cancer. World J. Gastroenterol. 2015, 21, 6271–6279. [Google Scholar] [CrossRef] [PubMed]
  42. Skonieczna, M.; Hejmo, T.; Poterala-Hejmo, A.; Cieslar-Pobuda, A.; Buldak, R.J. NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells. Oxid Med. Cell. Longev. 2017, 2017, 9420539. [Google Scholar] [CrossRef] [PubMed]
  43. Grasso, C.; Jansen, G.; Giovannetti, E. Drug resistance in pancreatic cancer: Impact of altered energy metabolism. Crit. Rev. Oncol. Hematol. 2017, 114, 139–152. [Google Scholar] [CrossRef] [PubMed]
  44. Wang, P.; Sun, Y.C.; Lu, W.H.; Huang, P.; Hu, Y. Selective killing of K-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase. Chin. J. Cancer 2015, 34, 166–176. [Google Scholar] [CrossRef] [PubMed]
  45. Garrido-Laguna, I.; Hidalgo, M. Pancreatic cancer: From state-of-the-art treatments to promising novel therapies. Nat. Rev. Clin. Oncol. 2015, 12, 319–334. [Google Scholar] [CrossRef] [PubMed]
  46. Weyemi, U.; Redon, C.E.; Parekh, P.R.; Dupuy, C.; Bonner, W.M. NADPH Oxidases NOXs and DUOXs as putative targets for cancer therapy. Anti-Cancer Agents Med. Chem. 2013, 13, 502–514. [Google Scholar]
  47. Che, M.; Wang, R.; Li, X.; Wang, H.Y.; Zheng, X.F.S. Expanding roles of superoxide dismutases in cell regulation and cancer. Drug Discov. Today 2016, 21, 143–149. [Google Scholar] [CrossRef]
  48. Dhar, S.K.; St Clair, D.K. Manganese superoxide dismutase regulation and cancer. Free Radic. Biol. Med. 2012, 52, 2209–2222. [Google Scholar] [CrossRef]
  49. Papa, L.; Hahn, M.; Marsh, E.L.; Evans, B.S.; Germain, D. SOD2 to SOD1 switch in breast cancer. J. Biol. Chem. 2014, 289, 5412–5416. [Google Scholar] [CrossRef]
  50. Glasauer, A.; Sena, L.A.; Diebold, L.P.; Mazar, A.P.; Chandel, N.S. Targeting SOD1 reduces experimental non-small-cell lung cancer. J. Clin. Investig. 2014, 124, 117–128. [Google Scholar] [CrossRef]
  51. Oberley, L.W.; Buettner, G.R. Role of superoxide dismutase in cancer: A review. Cancer Res. 1979, 39, 1141–1149. [Google Scholar] [PubMed]
  52. Hempel, N.; Carrico, P.M.; Melendez, J.A. Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis. Anti-Cancer Agents Med. Chem. 2011, 11, 191–201. [Google Scholar] [CrossRef]
  53. Hempel, N.; Melendez, J.A. Intracellular redox status controls membrane localization of pro- and anti-migratory signaling molecules. Redox Biol. 2014, 2, 245–250. [Google Scholar] [CrossRef] [PubMed]
  54. Jung, I.; Kim, T.Y.; Kim-Ha, J. Identification of Drosophila SOD3 and its protective role against phototoxic damage to cells. FEBS Lett. 2011, 585, 1973–1978. [Google Scholar] [CrossRef] [PubMed]
  55. Fisher, A.B. Redox signaling across cell membranes. Antioxid. Redox Signal. 2009, 11, 1349–1356. [Google Scholar] [CrossRef] [PubMed]
  56. Fukai, T.; Folz, R.J.; Landmesser, U.; Harrison, D.G. Extracellular superoxide dismutase and cardiovascular disease. Cardiovasc. Res. 2002, 55, 239–249. [Google Scholar] [CrossRef]
  57. Glorieux, C.; Calderon, P.B. Catalase, a remarkable enzyme: Targeting the oldest antioxidant enzyme to find a new cancer treatment approach. Biol. Chem. 2017, 398, 1095–1108. [Google Scholar] [CrossRef] [PubMed]
  58. Glorieux, C.; Zamocky, M.; Sandoval, J.M.; Verrax, J.; Calderon, P.B. Regulation of catalase expression in healthy and cancerous cells. Free Radic. Biol. Med. 2015, 87, 84–97. [Google Scholar] [CrossRef] [PubMed]
  59. Rainis, T.; Maor, I.; Lanir, A.; Shnizer, S.; Lavy, A. Enhanced oxidative stress and leucocyte activation in neoplastic tissues of the colon. Dig. Dis. Sci. 2007, 52, 526–530. [Google Scholar] [CrossRef]
  60. Hwang, T.S.; Choi, H.K.; Han, H.S. Differential expression of manganese superoxide dismutase, copper/zinc superoxide dismutase, and catalase in gastric adenocarcinoma and normal gastric mucosa. Eur. J. Surg. Oncol. 2007, 33, 474–479. [Google Scholar] [CrossRef]
  61. Sander, C.S.; Hamm, F.; Elsner, P.; Thiele, J.J. Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br. J. Dermatol. 2003, 148, 913–922. [Google Scholar] [CrossRef] [PubMed]
  62. Yen, H.C.; Li, S.H.; Majima, H.J.; Huang, Y.H.; Chen, C.P.; Liu, C.C.; Tu, Y.C.; Chen, C.W. Up-regulation of antioxidant enzymes and coenzyme Q(10) in a human oral cancer cell line with acquired bleomycin resistance. Free Radic. Res. 2011, 45, 707–716. [Google Scholar] [CrossRef] [PubMed]
  63. Kuramitsu, Y.; Taba, K.; Ryozawa, S.; Yoshida, K.; Zhang, X.; Tanaka, T.; Maehara, S.I.; Maehara, Y.; Sakaida, I.; Nakamura, K. Identification of up- and down-regulated proteins in gemcitabine-resistant pancreatic cancer cells using two-dimensional gel electrophoresis and mass spectrometry. Anti-Cancer Res. 2010, 30, 3367–3372. [Google Scholar]
  64. Xu, H.; Choi, S.M.; An, C.S.; Min, Y.D.; Kim, K.C.; Kim, K.J.; Choi, C.H. Concentration-dependent collateral sensitivity of cisplatin-resistant gastric cancer cell sublines. Biochem. Biophys. Res. Commun. 2005, 328, 618–622. [Google Scholar] [CrossRef] [PubMed]
  65. Xu, B.H.; Gupta, V.; Singh, S.V. Characterization of a human bladder cancer cell line selected for resistance to mitomycin C. Int. J. Cancer 1994, 58, 686–692. [Google Scholar] [CrossRef] [PubMed]
  66. Kim, Y.; Jang, H.H. Role of Cytosolic 2-Cys Prx1 and Prx2 in Redox Signaling. Antioxidants 2019, 8, 169. [Google Scholar] [CrossRef] [PubMed]
  67. Sharapov, M.G.; Novoselov, V.I. Catalytic and Signaling Role of Peroxiredoxins in Carcinogenesis. Biochemistry 2019, 84, 79–100. [Google Scholar] [CrossRef]
  68. Knoops, B.; Goemaere, J.; Van der Eecken, V.; Declercq, J.P. Peroxiredoxin 5: Structure, mechanism, and function of the mammalian atypical 2-Cys peroxiredoxin. Antioxid. Redox Signal. 2011, 15, 817–829. [Google Scholar] [CrossRef]
  69. Fisher, A.B. Peroxiredoxin 6: A bifunctional enzyme with glutathione peroxidase and phospholipase A(2) activities. Antioxid. Redox Signal. 2011, 15, 831–844. [Google Scholar] [CrossRef]
  70. Nicolussi, A.; D’Inzeo, S.; Capalbo, C.; Giannini, G.; Coppa, A. The role of peroxiredoxins in cancer. Mol. Clin. Oncol. 2017, 6, 139–153. [Google Scholar] [CrossRef]
  71. Park, Y.H.; Kim, S.U.; Kwon, T.H.; Kim, J.M.; Song, I.S.; Shin, H.J.; Lee, B.K.; Bang, D.H.; Lee, S.J.; Lee, D.S. Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway. Oncogene 2016, 35, 3503–3513. [Google Scholar] [CrossRef] [PubMed]
  72. Lee, D.J.; Kang, D.H.; Choi, M.; Choi, Y.J.; Lee, J.Y.; Park, J.H.; Park, Y.J.; Lee, K.W.; Kang, S.W. Peroxiredoxin-2 represses melanoma metastasis by increasing E-Cadherin/beta-Catenin complexes in adherens junctions. Cancer Res. 2013, 73, 4744–4757. [Google Scholar] [CrossRef] [PubMed]
  73. Giudice, A.; Arra, C.; Turco, M.C. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol. Biol. 2010, 647, 37–74. [Google Scholar] [PubMed]
  74. Giudice, A.; Barbieri, A.; Bimonte, S.; Cascella, M.; Cuomo, A.; Crispo, A.; D’Arena, G.; Galdiero, M.; Della Pepa, M.E.; Botti, G.; et al. Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms. Onco Targets Ther. 2019, 12, 4937–4953. [Google Scholar] [CrossRef] [PubMed]
  75. Grewal, G.K.; Kukal, S.; Kanojia, N.; Saso, L.; Kukreti, S.; Kukreti, R. Effect of Oxidative Stress on ABC Transporters: Contribution to Epilepsy Pharmacoresistance. Molecules 2017, 22, 365. [Google Scholar] [CrossRef] [PubMed]
  76. Bai, X.; Chen, Y.; Hou, X.; Huang, M.; Jin, J. Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters. Drug Metab. Rev. 2016, 48, 541–567. [Google Scholar] [CrossRef] [PubMed]
  77. Brufsky, A.M. Current Approaches and Emerging Directions in HER2-resistant Breast Cancer. Breast Cancer 2014, 8, 109–118. [Google Scholar] [CrossRef]
  78. Ganan-Gomez, I.; Wei, Y.; Yang, H.; Boyano-Adanez, M.C.; Garcia-Manero, G. Oncogenic functions of the transcription factor Nrf2. Free Radic. Biol. Med. 2013, 65, 750–764. [Google Scholar] [CrossRef]
  79. Rushworth, S.A.; Macewan, D.J. The role of nrf2 and cytoprotection in regulating chemotherapy resistance of human leukemia cells. Cancers 2011, 3, 1605–1621. [Google Scholar] [CrossRef]
  80. Hayes, J.D.; McMahon, M. NRF2 and KEAP1 mutations: Permanent activation of an adaptive response in cancer. Trends Biochem. Sci. 2009, 34, 176–188. [Google Scholar] [CrossRef]
  81. Marin, J.J.G.; Cives-Losada, C.; Asensio, M.; Lozano, E.; Briz, O.; Macias, R.I.R. Mechanisms of Anticancer Drug Resistance in Hepatoblastoma. Cancers 2019, 11, 407. [Google Scholar] [CrossRef] [PubMed]
  82. Housman, G.; Byler, S.; Heerboth, S.; Lapinska, K.; Longacre, M.; Snyder, N.; Sarkar, S. Drug resistance in cancer: An overview. Cancers 2014, 6, 1769–1792. [Google Scholar] [CrossRef] [PubMed]
  83. Bruno, P.M.; Liu, Y.; Park, G.Y.; Murai, J.; Koch, C.E.; Eisen, T.J.; Pritchard, J.R.; Pommier, Y.; Lippard, S.J.; Hemann, M.T. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat. Med. 2017, 23, 461–471. [Google Scholar] [CrossRef] [PubMed]
  84. Zhang, Y.; Huang, L.; Shi, H.; Chen, H.; Tao, J.; Shen, R.; Wang, T. Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance. Cancer Sci. 2018, 109, 94–102. [Google Scholar] [CrossRef] [PubMed]
  85. Shi, Y.; Tang, B.; Yu, P.W.; Tang, B.; Hao, Y.X.; Lei, X.; Luo, H.X.; Zeng, D.Z. Autophagy protects against oxaliplatin-induced cell death via ER stress and ROS in Caco-2 cells. PLoS ONE 2012, 7, e51076. [Google Scholar] [CrossRef] [PubMed]
  86. Ding, Z.B.; Hui, B.; Shi, Y.H.; Zhou, J.; Peng, Y.F.; Gu, C.Y.; Yang, H.; Shi, G.M.; Ke, A.W.; Wang, X.Y. Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. Clin. Cancer Res. 2011, 17, 6229–6238. [Google Scholar] [CrossRef]
  87. Canta, A.; Pozzi, E.; Carozzi, V.A. Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN). Toxics 2015, 3, 198–223. [Google Scholar] [CrossRef]
  88. Kelley, M.R.; Jiang, Y.; Guo, C.; Reed, A.; Meng, H.; Vasko, M.R. Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy. PLoS ONE 2014, 9, e106485. [Google Scholar] [CrossRef]
  89. Plasencia, C.; Martinez-Balibrea, E.; Martinez-Cardus, A.; Quinn, D.I.; Abad, A.; Neamati, N. Expression analysis of genes involved in oxaliplatin response and development of oxaliplatin-resistant HT29 colon cancer cells. Int. J. Oncol. 2006, 29, 225–235. [Google Scholar] [CrossRef]
  90. Pirpour Tazehkand, A.; Akbarzadeh, M.; Velaie, K.; Sadeghi, M.R.; Samadi, N. The role of Her2-Nrf2 axis in induction of oxaliplatin resistance in colon cancer cells. Biomed. Pharmacother. 2018, 103, 755–766. [Google Scholar] [CrossRef]
  91. Chian, S.; Li, Y.Y.; Wang, X.J.; Tang, X.W. Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway. Asian Pac. J. Cancer Prev. 2014, 15, 2911–2916. [Google Scholar] [CrossRef] [PubMed]
  92. Robinson, S.M.; Mann, J.; Vasilaki, A.; Mathers, J.; Burt, A.D.; Oakley, F.; White, S.A.; Mann, D.A. Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model. J. Hepatol. 2013, 59, 318–326. [Google Scholar] [CrossRef] [PubMed]
  93. Longley, D.B.; Harkin, D.P.; Johnston, P.G. 5-fluorouracil: Mechanisms of action and clinical strategies. Nat. Rev. Cancer 2003, 3, 330–338. [Google Scholar] [CrossRef] [PubMed]
  94. Yao, C.W.; Kang, K.A.; Piao, M.J.; Ryu, Y.S.; Fernando, P.; Oh, M.C.; Park, J.E.; Shilinkova, K.; Na, S.Y.; Jeong, S.U.; et al. Reduced Autophagy in 5-Fluorouracil Resistant Colon Cancer Cells. Biomol. Ther. (Seoul) 2017, 25, 315–320. [Google Scholar] [CrossRef] [PubMed]
  95. Kang, K.A.; Piao, M.J.; Kim, K.C.; Kang, H.K.; Chang, W.Y.; Park, I.C.; Keum, Y.S.; Surh, Y.J.; Hyun, J.W. Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: Involvement of TET-dependent DNA demethylation. Cell Death Dis. 2014, 5, e1183. [Google Scholar] [CrossRef] [PubMed]
  96. Kang, K.A.; Ryu, Y.S.; Piao, M.J.; Shilnikova, K.; Kang, H.K.; Yi, J.M.; Boulanger, M.; Paolillo, R.; Bossis, G.; Yoon, S.Y.; et al. DUOX2-mediated production of reactive oxygen species induces epithelial mesenchymal transition in 5-fluorouracil resistant human colon cancer cells. Redox Biol. 2018, 17, 224–235. [Google Scholar] [CrossRef]
  97. Kim, J.K.; Kang, K.A.; Piao, M.J.; Ryu, Y.S.; Han, X.; Fernando, P.M.; Oh, M.C.; Park, J.E.; Shilnilova, K.; Boo, S.Y.; et al. Endoplasmic reticulum stress induces 5-fluorouracil resistance in human colon cancer cells. Environ. Toxicol. Pharmacol. 2016, 44, 128–133. [Google Scholar] [CrossRef]
  98. Chan, J.Y.; Phoo, M.S.; Clement, M.V.; Pervaiz, S.; Lee, S.C. Resveratrol displays converse dose-related effects on 5-fluorouracil-evoked colon cancer cell apoptosis: The roles of caspase-6 and p53. Cancer Biol. Ther. 2008, 7, 1305–1312. [Google Scholar] [CrossRef]
  99. Hwang, P.M.; Bunz, F.; Yu, J.; Rago, C.; Chan, T.A.; Murphy, M.P.; Kelso, G.F.; Smith, R.A.; Kinzler, K.W.; Vogelstein, B. Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nat. Med. 2001, 7, 1111–1117. [Google Scholar] [CrossRef]
  100. Zhang, N.; Yin, Y.; Xu, S.J.; Chen, W.S. 5-Fluorouracil: Mechanisms of resistance and reversal strategies. Molecules 2008, 13, 1551–1569. [Google Scholar] [CrossRef]
  101. Shin, Y.K.; Yoo, B.C.; Chang, H.J.; Jeon, E.; Hong, S.H.; Jung, M.S.; Lim, S.J.; Park, J.G. Down-regulation of mitochondrial F1F0-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance. Cancer Res. 2005, 65, 3162–3170. [Google Scholar] [CrossRef] [PubMed]
  102. Hwang, I.T.; Chung, Y.M.; Kim, J.J.; Chung, J.S.; Kim, B.S.; Kim, H.J.; Kim, J.S.; Yoo, Y.D. Drug resistance to 5-FU linked to reactive oxygen species modulator 1. Biochem. Biophys. Res. Commun. 2007, 359, 304–310. [Google Scholar] [CrossRef] [PubMed]
  103. Shi, L.; Wu, L.; Chen, Z.; Yang, J.; Chen, X.; Yu, F.; Zheng, F.; Lin, X. MiR-141 Activates Nrf2-Dependent Antioxidant Pathway via Down-Regulating the Expression of Keap1 Conferring the Resistance of Hepatocellular Carcinoma Cells to 5-Fluorouracil. Cell. Physiol. Biochem. 2015, 35, 2333–2348. [Google Scholar] [CrossRef] [PubMed]
  104. Del Vecchio, C.A.; Feng, Y.; Sokol, E.S.; Tillman, E.J.; Sanduja, S.; Reinhardt, F.; Gupta, P.B. De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling. PLoS Biol. 2014, 12, e1001945. [Google Scholar] [CrossRef] [PubMed]
  105. Hu, X.F.; Yao, J.; Gao, S.G.; Wang, X.S.; Peng, X.Q.; Yang, Y.T.; Feng, X.S. Nrf2 overexpression predicts prognosis and 5-FU resistance in gastric cancer. Asian Pac. J. Cancer Prev. 2013, 14, 5231–5235. [Google Scholar] [CrossRef] [PubMed]
  106. Kang, K.A.; Piao, M.J.; Ryu, Y.S.; Kang, H.K.; Chang, W.Y.; Keum, Y.S.; Hyun, J.W. Interaction of DNA demethylase and histone methyltransferase upregulates Nrf2 in 5-fluorouracil-resistant colon cancer cells. Oncotarget 2016, 7, 40594–40620. [Google Scholar] [CrossRef]
  107. Akhdar, H.; Loyer, P.; Rauch, C.; Corlu, A.; Guillouzo, A.; Morel, F. Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells. Eur. J. Cancer 2009, 45, 2219–2227. [Google Scholar] [CrossRef]
  108. Alimbetov, D.; Askarova, S.; Umbayev, B.; Davis, T.; Kipling, D. Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells. Int. J. Mol. Sci. 2018, 19, 1690. [Google Scholar] [CrossRef]
  109. Jiang, J.; Wang, K.; Chen, Y.; Chen, H.; Nice, E.C.; Huang, C. Redox regulation in tumor cell epithelial-mesenchymal transition: Molecular basis and therapeutic strategy. Signal Transduct. Target. Ther. 2017, 2, 17036. [Google Scholar] [CrossRef]
  110. Shen, Y.; Yang, J.; Zhao, J.; Xiao, C.; Xu, C.; Xiang, Y. The switch from ER stress-induced apoptosis to autophagy via ROS-mediated JNK/p62 signals: A survival mechanism in methotrexate-resistant choriocarcinoma cells. Exp. Cell Res. 2015, 334, 207–218. [Google Scholar] [CrossRef]
  111. Dayem, A.A.; Choi, H.Y.; Kim, J.H.; Cho, S.G. Role of oxidative stress in stem, cancer, and cancer stem cells. Cancers 2010, 2, 859–884. [Google Scholar] [CrossRef] [PubMed]
  112. Burhans, W.C.; Heintz, N.H. The cell cycle is a redox cycle: Linking phase-specific targets to cell fate. Free Radic. Biol. Med. 2009, 47, 1282–1293. [Google Scholar] [CrossRef] [PubMed]
  113. Salaroglio, I.C.; Panada, E.; Moiso, E.; Buondonno, I.; Provero, P.; Rubinstein, M.; Kopecka, J.; Riganti, C. PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy. Mol. Cancer 2017, 16, 91. [Google Scholar] [CrossRef] [PubMed]
  114. Madden, E.; Logue, S.E.; Healy, S.J.; Manie, S.; Samali, A. The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance. Biol. Cell 2019, 111, 1–17. [Google Scholar] [CrossRef] [PubMed]
  115. Huang, Z.; Zhou, L.; Chen, Z.; Nice, E.C.; Huang, C. Stress management by autophagy: Implications for chemoresistance. Int. J. Cancer 2016, 139, 23–32. [Google Scholar] [CrossRef] [PubMed]
  116. Wang, M.; Kaufman, R.J. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer 2014, 14, 581–597. [Google Scholar] [CrossRef] [PubMed]
  117. Dufey, E.; Sepulveda, D.; Rojas-Rivera, D.; Hetz, C. Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview. Am. J. Physiol. Cell Physiol. 2014, 307, C582–C594. [Google Scholar] [CrossRef]
  118. Song, S.; Tan, J.; Miao, Y.; Zhang, Q. Crosstalk of ER stress-mediated autophagy and ER-phagy: Involvement of UPR and the core autophagy machinery. J. Cell. Physiol. 2018, 233, 3867–3874. [Google Scholar] [CrossRef]
  119. Healy, S.J.; Gorman, A.M.; Mousavi-Shafaei, P.; Gupta, S.; Samali, A. Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur. J. Pharmacol. 2009, 625, 234–246. [Google Scholar] [CrossRef]
  120. He, L.; He, T.; Farrar, S.; Ji, L.; Liu, T.; Ma, X. Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species. Cell Physiol. Biochem. 2017, 44, 532–553. [Google Scholar] [CrossRef]
  121. Ma, X.; Zhang, S.; He, L.; Rong, Y.; Brier, L.W.; Sun, Q.; Liu, R.; Fan, W.; Chen, S.; Yue, S.; et al. MTORC1-mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy. Autophagy 2017, 13, 592–607. [Google Scholar] [CrossRef] [PubMed]
  122. Woo, J.; Park, E.; Dinesh-Kumar, S.P. Differential processing of Arabidopsis ubiquitin-like Atg8 autophagy proteins by Atg4 cysteine proteases. Proc. Natl. Acad. Sci. USA 2014, 111, 863–868. [Google Scholar] [CrossRef] [PubMed]
  123. Azad, M.B.; Chen, Y.; Gibson, S.B. Regulation of autophagy by reactive oxygen species (ROS): Implications for cancer progression and treatment. Antioxid. Redox Signal. 2009, 11, 777–790. [Google Scholar] [CrossRef] [PubMed]
  124. Scherz-Shouval, R.; Shvets, E.; Fass, E.; Shorer, H.; Gil, L.; Elazar, Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 2007, 26, 1749–1760. [Google Scholar] [CrossRef] [PubMed]
  125. Zhang, X.; Cheng, X.; Yu, L.; Yang, J.; Calvo, R.; Patnaik, S.; Hu, X.; Gao, Q.; Yang, M.; Lawas, M.; et al. MCOLN1 is a ROS sensor in lysosomes that regulates autophagy. Nat. Commun. 2016, 7, 12109. [Google Scholar] [CrossRef] [PubMed]
  126. Scherz-Shouval, R.; Shvets, E.; Elazar, Z. Oxidation as a post-translational modification that regulates autophagy. Autophagy 2007, 3, 371–373. [Google Scholar] [CrossRef] [PubMed]
  127. Gines, A.; Bystrup, S.; Ruiz de Porras, V.; Guardia, C.; Musulen, E.; Martinez-Cardus, A.; Manzano, J.L.; Layos, L.; Abad, A.; Martinez-Balibrea, E. PKM2 Subcellular Localization Is Involved in Oxaliplatin Resistance Acquisition in HT29 Human Colorectal Cancer Cell Lines. PLoS ONE 2015, 10, e0123830. [Google Scholar] [CrossRef]
  128. Delgado, M.; Tesfaigzi, Y. Is BMF central for anoikis and autophagy? Autophagy 2014, 10, 168–169. [Google Scholar] [CrossRef]
  129. Tischner, D.; Manzl, C.; Soratroi, C.; Villunger, A.; Krumschnabel, G. Necrosis-like death can engage multiple pro-apoptotic Bcl-2 protein family members. Apoptosis 2012, 17, 1197–1209. [Google Scholar] [CrossRef]
  130. Grespi, F.; Soratroi, C.; Krumschnabel, G.; Sohm, B.; Ploner, C.; Geley, S.; Hengst, L.; Hacker, G.; Villunnger, A. BH3-only protein Bmf mediates apoptosis upon inhibition of CAP-dependent protein synthesis. Cell Death Differ. 2010, 17, 1672–1683. [Google Scholar] [CrossRef]
  131. Du, H.; Yang, W.; Chen, L.; Shi, M.; Seewoo, V.; Wang, J.; Lin, A.; Liu, Z.; Qui, W. Role of autophagy in resistance to oxaliplatin in hepatocellular carcinoma cells. Oncol. Rep. 2012, 27, 143–150. [Google Scholar] [PubMed]
  132. Das, C.K.; Linder, B.; Bonn, F.; Rothweiler, F.; Dikic, I.; Michaelis, M.; Cinatl, J.; Mandal, M.; Kogel, D. BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells. Neoplasia 2018, 20, 263–279. [Google Scholar] [CrossRef] [PubMed]
  133. Sherr, C.J.; Roberts, J.M. CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev. 1999, 13, 1501–1512. [Google Scholar] [CrossRef] [PubMed]
  134. Campbell, P.J.; Yachida, S.; Mudie, L.J.; Stephens, P.J.; Pleasance, E.D.; Stebbings, L.A.; Morsberger, L.A.; Latimer, C.; McLaren, S.; Lin, M.L.; et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 2010, 467, 1109–1113. [Google Scholar] [CrossRef]
  135. Menon, S.G.; Goswami, P.C. A redox cycle within the cell cycle: Ring in the old with the new. Oncogene 2007, 26, 1101–1109. [Google Scholar] [CrossRef] [PubMed]
  136. Maziere, C.; Trecherel, E.; Ausseil, J.; Louandre, C.; Maziere, J.C. Oxidized low density lipoprotein induces cyclin A synthesis. Involvement of ERK, JNK and NFkappaB. Atherosclerosis 2011, 218, 308–313. [Google Scholar] [CrossRef]
  137. Tickner, J.; Fan, L.M.; Du, J.; Meijles, D.; Li, J.M. Nox2-derived ROS in PPARgamma signaling and cell-cycle progression of lung alveolar epithelial cells. Free Radic. Biol. Med. 2011, 51, 763–772. [Google Scholar] [CrossRef]
  138. Havens, C.G.; Ho, A.; Yoshioka, N.; Dowdy, S.F. Regulation of late G1/S phase transition and APC Cdh1 by reactive oxygen species. Mol. Cell. Biol. 2006, 26, 4701–4711. [Google Scholar] [CrossRef]
  139. Deshpande, S.S.; Irani, K. Oxidant signalling in carcinogenesis: A commentary. Hum. Exp. Toxicol. 2002, 21, 63–64. [Google Scholar] [CrossRef]
  140. Stamatakos, M.; Palla, V.; Karaiskos, I.; Xiromeritis, K.; Alexiou, I.; Pateras, I.; Kontzoglou, K. Cell cyclins: Triggering elements of cancer or not? World J. Surg. Oncol. 2010, 8, 111. [Google Scholar] [CrossRef]
  141. Fu, M.; Wang, C.; Li, Z.; Sakamaki, T.; Pestell, R.G. Minireview: Cyclin D1: Normal and abnormal functions. Endocrinology 2004, 145, 5439–5447. [Google Scholar] [CrossRef] [PubMed]
  142. Imanishi, Y.; Hosokawa, Y.; Yoshimoto, K.; Schipani, E.; Mallya, S.; Papanikolaou, A.; Kifor, O.; Tokura, T.; Sablosky, M.; Ledgard, F.; et al. Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J. Clin. Investig. 2001, 107, 1093–1102. [Google Scholar] [CrossRef] [PubMed]
  143. Yasui, M.; Yamamoto, H.; Ngan, C.Y.; Damdinsuren, B.; Sugita, Y.; Fukunaga, H.; Gu, J.; Maeda, M.; Takemasa, I.; Ikeda, M.; et al. Antisense to cyclin D1 inhibits vascular endothelial growth factor-stimulated growth of vascular endothelial cells: Implication of tumor vascularization. Clin. Cancer Res. 2006, 12, 4720–4729. [Google Scholar] [CrossRef] [PubMed]
  144. Sakamaki, T.; Casimiro, M.C.; Ju, X.; Quong, A.A.; Katiyar, S.; Liu, M.; Jiao, X.; Li, A.; Zhang, X.; Lu, Y.; et al. Cyclin D1 determines mitochondrial function in vivo. Mol. Cell. Biol. 2006, 26, 5449–5469. [Google Scholar] [CrossRef] [PubMed]
  145. Hsu, H.H.; Chen, M.C.; Baskaran, R.; Lin, Y.M.; Day, C.H.; Lin, Y.J.; Tu, C.C.; Vijaya Padma, V.; Kuo, W.W.; Huang, C.Y. Oxaliplatin resistance in colorectal cancer cells is mediated via activation of ABCG2 to alleviate ER stress induced apoptosis. J. Cell Physiol. 2018, 233, 5458–5467. [Google Scholar] [CrossRef]
  146. El Khoury, F.; Corcos, L.; Durand, S.; Simon, B.; Le Jossic-Corcos, C. Acquisition of anticancer drug resistance is partially associated with cancer stemness in human colon cancer cells. Int. J. Oncol. 2016, 49, 2558–2568. [Google Scholar] [CrossRef] [PubMed]
  147. Guo, X.; Goessl, E.; Jin, G.; Collie-Duguid, E.S.; Cassidy, J.; Wang, W.; O’Brien, W. Cell cycle perturbation and acquired 5-fluorouracil chemoresistance. Anti-Cancer Res. 2008, 28, 9–14. [Google Scholar]
  148. Wang, W.B.; Yang, Y.; Zhao, Y.P.; Zhang, T.P.; Liao, Q.; Shu, H. Recent studies of 5-fluorouracil resistance in pancreatic cancer. World J. Gastroenterol. 2014, 20, 15682–15690. [Google Scholar] [CrossRef]
  149. Wang, W.; Cassidy, J.; O’Brien, V.; Ryan, K.M.; Collie-Duguid, E. Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004, 64, 8167–8176. [Google Scholar] [CrossRef]
  150. Li, M.H.; Ito, D.; Sanada, M.; Odani, T.; Hatori, M.; Iwase, M.; Nagumo, M. Effect of 5-fluorouracil on G1 phase cell cycle regulation in oral cancer cell lines. Oral Oncol. 2004, 40, 63–70. [Google Scholar] [CrossRef]
  151. Phi, L.T.H.; Sari, I.N.; Yang, Y.G.; Lee, S.H.; Jun, N.; Kim, K.S.; Lee, Y.K.; Kwon, H.Y. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int. 2018, 2018, 5416923. [Google Scholar] [CrossRef] [PubMed]
  152. Du, B.; Shim, J.S. Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules 2016, 21, 965. [Google Scholar] [CrossRef] [PubMed]
  153. Singh, A.; Settleman, J. EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene 2010, 29, 4741–4751. [Google Scholar] [CrossRef] [PubMed]
  154. Hermann, P.C.; Huber, S.L.; Herrler, T.; Aicher, A.; Ellwart, J.W.; Guba, M.; Bruns, C.J.; Heeschen, C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1, 313–323. [Google Scholar] [CrossRef] [PubMed]
  155. Wielenga, V.J.; Smits, R.; Korinek, V.; Smit, L.; Kielman, M.; Fodde, R.; Clevers, H.; Pals, S.T. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am. J. Pathol. 1999, 154, 515–523. [Google Scholar] [CrossRef]
  156. Shibue, T.; Weinberg, R.A. EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 2017, 14, 611–629. [Google Scholar] [CrossRef] [PubMed]
  157. Kojima, H.; Okumura, T.; Yamaguchi, T.; Miwa, T.; Shimada, Y.; Nagata, T. Enhanced cancer stem cell properties of a mitotically quiescent subpopulation of p75NTR-positive cells in esophageal squamous cell carcinoma. Int. J. Oncol. 2017, 51, 49–62. [Google Scholar] [CrossRef] [PubMed]
  158. Wang, J.; Liu, X.; Jiang, Z.; Li, L.; Cui, Z.; Gao, Y.; Kong, D.; Liu, X. A novel method to limit breast cancer stem cells in states of quiescence, proliferation or differentiation: Use of gel stress in combination with stem cell growth factors. Oncol. Lett. 2016, 12, 1355–1360. [Google Scholar] [CrossRef]
  159. Begicevic, R.R.; Falasca, M. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. Int. J. Mol. Sci. 2017, 18, 2362. [Google Scholar] [CrossRef]
  160. Jiao, L.; Li, D.D.; Yang, C.L.; Peng, R.Q.; Guo, Y.Q.; Zhang, X.S.; Zhu, X.F. Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer. Tumour Biol. 2016, 37, 8413–8423. [Google Scholar] [CrossRef]
  161. Yang, A.D.; Fan, F.; Camp, E.R.; van Buren, G.; Liu, W.; Somcio, R.; Gray, M.J.; Cheng, H.; Hoff, P.M.; Ellis, L.M. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin. Cancer Res. 2006, 12, 4147–4153. [Google Scholar] [CrossRef] [PubMed]
  162. Liao, X.; Bu, Y.; Jiang, S.; Chang, F.; Jia, F.; Xiao, X.; Song, G.; Zhang, M.; Ning, P.; Jia, Q. CCN2-MAPK-Id-1 loop feedback amplification is involved in maintaining stemness in oxaliplatin-resistant hepatocellular carcinoma. Hepatol. Int. 2019, 13, 440–453. [Google Scholar] [CrossRef]
  163. Yin, X.; Tang, B.; Li, J.H.; Wang, Y.; Zhang, L.; Xie, X.Y.; Zhang, B.H.; Qiu, S.J.; Wu, W.Z.; Ren, Z.G. ID1 promotes hepatocellular carcinoma proliferation and confers chemoresistance to oxaliplatin by activating pentose phosphate pathway. J. Exp. Clin. Cancer Res. 2017, 36, 166. [Google Scholar] [CrossRef] [PubMed]
  164. Dhar, A.; Ray, A. The CCN family proteins in carcinogenesis. Exp. Oncol. 2010, 32, 2–9. [Google Scholar] [PubMed]
  165. Yang, Y.; Yao, J.H.; Du, Q.Y.; Zhou, Y.C.; Yao, T.J.; Wu, Q.; Liu, J.; Ou, Y.R. Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT. Cancer Manag. Res. 2019, 11, 5133–5146. [Google Scholar] [CrossRef] [PubMed]
  166. Fujimoto, E.; Sato, H.; Shirai, S.; Nagashima, Y.; Fukumoto, K.; Hagiwara, H.; Negishi, E.; Ueno, K.; Omori, Y.; Yamasaki, H.; et al. Connexin32 as a tumor suppressor gene in a metastatic renal cell carcinoma cell line. Oncogene 2005, 24, 3684–3690. [Google Scholar] [CrossRef] [PubMed]
  167. Lin, L.; Li, X.; Pan, C.; Lin, W.; Shao, R.; Liu, Y.; Zhang, J.; Luo, Y.; Qian, K.; Shi, M.; et al. ATXN2L upregulated by epidermal growth factor promotes gastric cancer cell invasiveness and oxaliplatin resistance. Cell Death Dis. 2019, 10, 173. [Google Scholar] [CrossRef] [PubMed]
  168. Kaehler, C.; Isensee, J.; Nonhoff, U.; Terrey, M.; Hucho, T.; Lehrach, H.; Krobitsch, S. Ataxin-2-like is a regulator of stress granules and processing bodies. PLoS ONE 2012, 7, e50134. [Google Scholar] [CrossRef]
  169. Yang, D.; Wang, H.; Zhang, J.; Li, C.; Lu, Z.; Liu, J.; Lin, C.; Li, G.; Qian, H. In vitro characterization of stem cell-like properties of drug-resistant colon cancer subline. Oncol. Res. 2013, 21, 51–57. [Google Scholar] [CrossRef]
  170. Kim, A.Y.; Kwak, J.H.; Je, N.K.; Lee, Y.H.; Jung, Y.S. Epithelial-mesenchymal Transition is Associated with Acquired Resistance to 5-Fluorocuracil in HT-29 Colon Cancer Cells. Toxicol. Res. 2015, 31, 151–156. [Google Scholar] [CrossRef]
  171. Harada, K.; Ferdous, T.; Ueyama, Y. Establishment of 5-fluorouracil-resistant oral squamous cell carcinoma cell lines with epithelial to mesenchymal transition changes. Int. J. Oncol. 2014, 44, 1302–1308. [Google Scholar] [CrossRef] [PubMed]
  172. Sun, L.; Ke, J.; He, Z.; Chen, Z.; Huang, Q.; Ai, W.; Wang, G.; Wei, Y.; Zou, X.; Zhang, S.; et al. HES1 Promotes Colorectal Cancer Cell Resistance To 5-Fu by Inducing Of EMT and ABC Transporter Proteins. J. Cancer 2017, 8, 2802–2808. [Google Scholar] [CrossRef] [PubMed]
  173. Zhang, C.; Ma, Q.; Shi, Y.; Li, X.; Wang, M.; Wang, J.; Ge, J.; Chen, Z.; Wang, Z.; Jiang, H. A novel 5-fluorouracil-resistant human esophageal squamous cell carcinoma cell line Eca-109/5-FU with significant drug resistance-related characteristics. Oncol. Rep. 2017, 37, 2942–2954. [Google Scholar] [CrossRef]
  174. Vishnoi, K.; Mahata, S.; Tyagi, A.; Pandey, A.; Verma, G.; Jadli, M.; Singh, T.; Singh, S.M.; Bharti, A.C. Human papillomavirus oncoproteins differentially modulate epithelial-mesenchymal transition in 5-FU-resistant cervical cancer cells. Tumour Biol. 2016, 37, 13137–13154. [Google Scholar] [CrossRef] [PubMed]
  175. Zhang, W.; Feng, M.; Zheng, G.; Chen, Y.; Wang, X.; Pen, B.; Yin, J.; Yu, Y.; He, Z. Chemoresistance to 5-fluorouracil induces epithelial-mesenchymal transition via up-regulation of Snail in MCF7 human breast cancer cells. Biochem. Biophys. Res. Commun. 2012, 417, 679–685. [Google Scholar] [CrossRef] [PubMed]
  176. Izumiya, M.; Kabashima, A.; Higuchi, H.; Igarashi, T.; Sakai, G.; Iizuka, H.; Nakamura, S.; Adachi, M.; Hamamoto, Y.; Funakoshi, S.; et al. Chemoresistance is associated with cancer stem cell-like properties and epithelial-to-mesenchymal transition in pancreatic cancer cells. Anti-Cancer Res. 2012, 32, 3847–3853. [Google Scholar]
  177. Miyoshi, S.; Tsugawa, H.; Matsuzaki, J.; Hirata, K.; Mori, H.; Saya, H.; Kanai, T.; Suzuki, H. Inhibiting xCT Improves 5-Fluorouracil Resistance of Gastric Cancer Induced by CD44 Variant 9 Expression. Anti-Cancer Res. 2018, 38, 6163–6170. [Google Scholar] [CrossRef] [PubMed]
  178. Terzioglu, G.; Turksoy, O.; Bayrak, O.F. Identification of An mtDNA Setpoint Associated with Highest Levels of CD44 Positivity and Chemoresistance in HGC-27 and MKN-45 Gastric Cancer Cell Lines. Cell J. 2018, 20, 312–317. [Google Scholar] [PubMed]
  179. Denise, C.; Paoli, P.; Calvani, M.; Taddei, M.L.; Giannoni, E.; Kopetz, S.; Kazmi, S.M.; Pia, M.M.; Pettazzoni, P.; Sacco, E.; et al. 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget 2015, 6, 41706–41721. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Redox homeostasis between generation and elimination of reactive oxygen species (ROS). ROS production is regulated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) in membranes, the electron transport chain (ETC) of the adenosine triphosphate (ATP) synthesis process in mitochondria, and the protein synthesis process in endoplasmic reticulum (ER) during O2 consumption. Alternative levels of ROS induce DNA damage or transcription factors (TFs)-mediated gene expression in the nucleus. The superoxide anion (O2) produced intracellularly is neutralized to hydrogen peroxide (H2O2) by the superoxide dismutase (SOD) family. H2O2 are detoxified to H2O by catalase and peroxiredoxin (Prx). ROS regulate cellular processes such as proliferation, apoptosis, chemoresistance, and differentiation through a variety of signaling pathways.
Figure 1. Redox homeostasis between generation and elimination of reactive oxygen species (ROS). ROS production is regulated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) in membranes, the electron transport chain (ETC) of the adenosine triphosphate (ATP) synthesis process in mitochondria, and the protein synthesis process in endoplasmic reticulum (ER) during O2 consumption. Alternative levels of ROS induce DNA damage or transcription factors (TFs)-mediated gene expression in the nucleus. The superoxide anion (O2) produced intracellularly is neutralized to hydrogen peroxide (H2O2) by the superoxide dismutase (SOD) family. H2O2 are detoxified to H2O by catalase and peroxiredoxin (Prx). ROS regulate cellular processes such as proliferation, apoptosis, chemoresistance, and differentiation through a variety of signaling pathways.
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Figure 2. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox-homeostasis and chemoresistance in cells. Nrf2 induces antioxidant proteins such as superoxide dismutase (SOD), catalase (CAT), peroxiredoxin (Prx), glutathione reductase (GR), thioredoxin reductase (TR), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO). Multidrug resistance protein 1 (MRP1) and breast cancer resistance protein/ATP-binding cassette subfamily G member 2 (BCRP/ABCG2) are related with drug transport and are upregulated by activation of Nrf2.
Figure 2. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox-homeostasis and chemoresistance in cells. Nrf2 induces antioxidant proteins such as superoxide dismutase (SOD), catalase (CAT), peroxiredoxin (Prx), glutathione reductase (GR), thioredoxin reductase (TR), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO). Multidrug resistance protein 1 (MRP1) and breast cancer resistance protein/ATP-binding cassette subfamily G member 2 (BCRP/ABCG2) are related with drug transport and are upregulated by activation of Nrf2.
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Figure 3. Redox homeostasis between generation and elimination of ROS. Cancer cells increase ROS-mediated apoptosis when exposed to chemotherapy treatments. Some cancer cells adapt to fluctuating ROS states through chemoresistance mechanisms. Activation of autophagy by ER stress gets rid of damaged organelles and protein aggregation. Cell cycle activation by the ignored entrance of the G0 phase increases cell proliferation in cancers. Epithelial-mesenchymal transition (EMT) enhances migration to other organs for the escapement of damaging environments. Cancer stem-like cells (CSCs) increase the expression of drug metabolic enzymes/transporters for cell survival from drug-mediated apoptosis. The specific microenvironment, called the niche, of CSCs are protected from chemotherapy. These mechanisms lead to the birth of chemoresistant cancer cells.
Figure 3. Redox homeostasis between generation and elimination of ROS. Cancer cells increase ROS-mediated apoptosis when exposed to chemotherapy treatments. Some cancer cells adapt to fluctuating ROS states through chemoresistance mechanisms. Activation of autophagy by ER stress gets rid of damaged organelles and protein aggregation. Cell cycle activation by the ignored entrance of the G0 phase increases cell proliferation in cancers. Epithelial-mesenchymal transition (EMT) enhances migration to other organs for the escapement of damaging environments. Cancer stem-like cells (CSCs) increase the expression of drug metabolic enzymes/transporters for cell survival from drug-mediated apoptosis. The specific microenvironment, called the niche, of CSCs are protected from chemotherapy. These mechanisms lead to the birth of chemoresistant cancer cells.
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