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Cisplatin in Cancer Therapy: Molecular Mechanisms of Action
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Cisplatin in Cancer Therapy: Molecular Mechanisms of Action

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 118032

Special Issue Editors

Dr. Nicola Margiotta

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Guest Editor
Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy
Interests: medicinal inorganic chemistry; organometallic chemistry; metal-based complexes; antitumor platinum drugs; drug delivery of antitumor drugs by inorganic nanocarriers
Special Issues, Collections and Topics in MDPI journals
Dr. James D. Hoeschele

E-Mail Website
Guest Editor
Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, USA
Interests: medicinal inorganic chemistry; organometallic chemistry; metal-based complexes; antitumor platinum drugs; drug delivery of antitumor drugs by inorganic nanocarriers
Special Issues, Collections and Topics in MDPI journals
Dr. Valentina Gandin

E-Mail Website
Guest Editor
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
Interests: thioredoxin reductase; cytotoxicity; anticancer agents; drug resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Although it has been 40 years since the FDA approved the use of cisplatin in the treatment of cancer (an event recently celebrated at Michigan State University in August), the mechanism of action of this drug is not yet fully elucidated. Definitive information about the mechanism of action of cisplatin includes four key steps: (1) cellular uptake, (2) activation by aquation, (3) DNA binding, and (4) the processing of DNA lesions leading to cancer cell death. Evidence correlating the pharmacological effect of cisplatin with its capability to damage the structure of DNA is irrefutable, but the intimate connections between the causes and the effects (especially as relates to step 4) have not been fully demonstrated. Despite this deficiency, 50% of all cancer chemotherapeutic treatments include a platinum drug, either cisplatin or carboplatin and oxaliplatin. Complete elucidation of the mechanism of action of platinum-based drugs is a fundamental and high-priority task that could potentially allow the amelioration or elimination of the severe side effects accompanying patient treatment. Another important challenge is to understand in detail the nature of the intracellular pathways that are affected by the platinum-DNA adducts, which are responsible for developing resistance to platinum drugs and for the differential response of tumors to these platinum drugs (i.e., cisplatin and oxaliplatin have different activities toward colorectal cancer). We think that the study of the molecular determinants involved in the mechanism of action of cisplatin and its analogs is an extremely important interdisciplinary field that requires the collaboration of chemists, biologists, pharmacologists, and physicians who, in some cases, do not always communicate on the same level. While the stakes are high, we are confident that the uncertainties in the mechanism of action of cisplatin can be elucidated in the next decade and in time to celebrate the 50th anniversary of the FDA’s approval of cisplatin.

Dr. Nicola Margiotta
Dr. James D. Hoeschele
Dr. Valentina Gandin
Guest Editors

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Keywords

  • Cisplatin
  • Antitumor platinum agents
  • Alkylating drugs
  • Platinum-DNA adducts
  • DNA-repair mechanisms
  • Apoptosis
  • Carboplatin
  • Oxaliplatin

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Published Papers (21 papers)

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19 pages, 2693 KiB  
Article
Synergistic or Additive Pharmacological Interactions between Magnoflorine and Cisplatin in Human Cancer Cells of Different Histological Origin
by Estera Okon, Jarogniew J. Luszczki, Wirginia Kukula-Koch, Marta Halasa, Agata Jarzab, Daariimaa Khurelbat, Andrzej Stepulak and Anna Wawruszak
Int. J. Mol. Sci. 2020, 21(8), 2848; https://doi.org/10.3390/ijms21082848 - 19 Apr 2020
Cited by 14 | Viewed by 3282
Abstract
Magnoflorine is an aporphine alkaloid present in plant species belonging to the Berberidaceae, Magnoliaceae, Menispermaceae, or Papaveraceae botanical families. The interest of magnoflorine has increased recently due to its multiplicity of pharmacological properties. The aim of this study was the analysis of combined [...] Read more.
Magnoflorine is an aporphine alkaloid present in plant species belonging to the Berberidaceae, Magnoliaceae, Menispermaceae, or Papaveraceae botanical families. The interest of magnoflorine has increased recently due to its multiplicity of pharmacological properties. The aim of this study was the analysis of combined anti-proliferative effect of magnoflorine and cisplatin and the assessment of drug–drug pharmacological interaction between these agents using isobolographic method in MDA-MB-468 human breast, NCIH1299 lung, TE671 rhabdomyosarcoma, or T98G glioblastoma cancer cell lines. Magnoflorine in combination with cisplatin at a fixed ratio of 1:1 augmented their anticancer action and yielded synergistic or additive pharmacological interactions by means of isobolographic method, therefore combined therapy using these two active agents can be a promising chemotherapy regimen in the treatment of some types of breast, lung, rhabdomyosarcoma, and glioblastoma cancers. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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13 pages, 2012 KiB  
Article
Caffeine and Cisplatin Effectively Targets the Metabolism of a Triple-Negative Breast Cancer Cell Line Assessed via Phasor-FLIM
by Stephanie M. Pascua, Gabrielle E. McGahey, Ning Ma, Justin J. Wang and Michelle A. Digman
Int. J. Mol. Sci. 2020, 21(7), 2443; https://doi.org/10.3390/ijms21072443 - 01 Apr 2020
Cited by 11 | Viewed by 3875
Abstract
Triple-negative tumor cells, a malignant subtype of breast cancer, lack a biologically targeted therapy. Given its DNA repair inhibiting properties, caffeine has been shown to enhance the effectiveness of specific tumor chemotherapies. In this work, we have investigated the effects of caffeine, cisplatin, [...] Read more.
Triple-negative tumor cells, a malignant subtype of breast cancer, lack a biologically targeted therapy. Given its DNA repair inhibiting properties, caffeine has been shown to enhance the effectiveness of specific tumor chemotherapies. In this work, we have investigated the effects of caffeine, cisplatin, and a combination of the two as potential treatments in energy metabolism for three cell lines, triple-negative breast cancer (MDA-MB-231), estrogen-receptor lacking breast cancer (MCF7) and breast epithelial cells (MCF10A) using a sensitive label-free approach, phasor-fluorescence lifetime imaging microscopy (phasor-FLIM). We found that solely using caffeine to treat MDA-MB-231 shifts their metabolism towards respiratory-chain phosphorylation with a lower ratio of free to bound NADH, and a similar trend is seen in MCF7. However, MDA-MB-231 cells shifted to a higher ratio of free to bound NADH when cisplatin was added. The combination of cisplatin and caffeine together reduced the survival rate for MDA-MD231 and shifted their energy metabolism to a higher fraction of bound NADH indicative of oxidative phosphorylation. The FLIM and viability results of MCF10A cells demonstrate that the treatments targeted cancer cells over the normal breast tissue. The identification of energy metabolism alteration could open up strategies of improving chemotherapy for malignant breast cancer. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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21 pages, 4435 KiB  
Article
Platinum(IV) Complexes of trans-1,2-diamino-4-cyclohexene: Prodrugs Affording an Oxaliplatin Analogue that Overcomes Cancer Resistance
by Paride Papadia, Katia Micoli, Alessandra Barbanente, Nicoletta Ditaranto, James D. Hoeschele, Giovanni Natile, Cristina Marzano, Valentina Gandin and Nicola Margiotta
Int. J. Mol. Sci. 2020, 21(7), 2325; https://doi.org/10.3390/ijms21072325 - 27 Mar 2020
Cited by 12 | Viewed by 4166
Abstract
Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. [...] Read more.
Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin; all IC50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5–8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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15 pages, 6750 KiB  
Article
Different Effects of Cisplatin and Transplatin on the Higher-Order Structure of DNA and Gene Expression
by Toshifumi Kishimoto, Yuko Yoshikawa, Kenichi Yoshikawa and Seiji Komeda
Int. J. Mol. Sci. 2020, 21(1), 34; https://doi.org/10.3390/ijms21010034 - 19 Dec 2019
Cited by 19 | Viewed by 9693
Abstract
Despite the effectiveness of cisplatin as an anticancer agent, its trans-isomer, transplatin, is clinically ineffective. Although both isomers target nuclear DNA, there is a large difference in the magnitude of their biological effects. Here, we compared their effects on gene expression in an [...] Read more.
Despite the effectiveness of cisplatin as an anticancer agent, its trans-isomer, transplatin, is clinically ineffective. Although both isomers target nuclear DNA, there is a large difference in the magnitude of their biological effects. Here, we compared their effects on gene expression in an in vitro luciferase assay and quantified their effects on the higher-order structure of DNA using fluorescence microscopy (FM) and atomic force microscopy (AFM). The inhibitory effect of cisplatin on gene expression was about 7 times that of transplatin. Analysis of the fluctuation autocorrelation function of the intrachain Brownian motion of individual DNA molecules showed that cisplatin increases the spring and damping constants of DNA by one order of magnitude and these visco-elastic characteristics tend to increase gradually over several hours. Transplatin had a weaker effect, which tended to decrease with time. These results agree with a stronger inhibitory effect of cisplatin on gene expression. We discussed the characteristic effects of the two compounds on the higher-order DNA structure and gene expression in terms of the differences in their binding to DNA. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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15 pages, 2353 KiB  
Article
Emetine Synergizes with Cisplatin to Enhance Anti-Cancer Efficacy against Lung Cancer Cells
by Ti-Hui Wu, Shan-Yueh Chang, Yu-Lueng Shih, Tsai-Wang Huang, Hung Chang and Ya-Wen Lin
Int. J. Mol. Sci. 2019, 20(23), 5914; https://doi.org/10.3390/ijms20235914 - 25 Nov 2019
Cited by 15 | Viewed by 3389
Abstract
Cisplatin is still the primary therapeutic choice for advanced lung cancers without driver mutations. The occurrence of cisplatin resistance is a major clinical problem in lung cancer treatment. The natural extracted agent emetine reportedly has anticancer effects. This study aimed to explore the [...] Read more.
Cisplatin is still the primary therapeutic choice for advanced lung cancers without driver mutations. The occurrence of cisplatin resistance is a major clinical problem in lung cancer treatment. The natural extracted agent emetine reportedly has anticancer effects. This study aimed to explore the possible role of emetine in cisplatin resistance. We used cell viability, Western blot, and Wnt reporter assays to show that emetine suppresses proliferation, β-catenin expression, and Wnt/β-catenin signaling in non-small cell lung cancer (NSCLC). The synergism of emetine and cisplatin was assessed by constructing isobolograms and calculating combination index (CI) values using the Chou-Talalay method. Emetine effectively synergized with cisplatin to suppress the proliferation of cancer cells. Furthermore, nuclear β-catenin and cancer stem cell-related markers were upregulated in the cisplatin-resistant subpopulation of CL1-0 cells. Emetine enhanced the anticancer efficacy of cisplatin and synergized with cisplatin in the cisplatin-resistant subpopulation of CL1-0 cells. Taken together, these data suggest that emetine could suppress the growth of NSCLC cells through the Wnt/β-catenin pathway and contribute to a synergistic effect in combination with cisplatin. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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17 pages, 2842 KiB  
Article
Additive Pharmacological Interaction between Cisplatin (CDDP) and Histone Deacetylase Inhibitors (HDIs) in MDA-MB-231 Triple Negative Breast Cancer (TNBC) Cells with Altered Notch1 Activity—An Isobolographic Analysis
by Anna Wawruszak, Jarogniew J. Luszczki, Joanna Kalafut, Karolina Okla, Marta Halasa, Adolfo Rivero-Muller and Andrzej Stepulak
Int. J. Mol. Sci. 2019, 20(15), 3663; https://doi.org/10.3390/ijms20153663 - 26 Jul 2019
Cited by 19 | Viewed by 4174
Abstract
The aim of this study was to investigate the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two histone deacetylase inhibitors (HDIs)—valproic acid (VPA) and vorinostat (SAHA) in the triple negative breast cancer (TNBC) cells. Stable breast [...] Read more.
The aim of this study was to investigate the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two histone deacetylase inhibitors (HDIs)—valproic acid (VPA) and vorinostat (SAHA) in the triple negative breast cancer (TNBC) cells. Stable breast cancer (BC) cell lines with increased and decreased activity of Notch1 were generated using a transfection method. The type of interaction between CDDP and the HDIs was determined by isobolographic analysis of cell proliferation in MDA-MB-231 cells with differential levels of Notch1 activity in vitro. The combination of CDDP/SAHA and CDDP/VPA in the MDA-MB-231 triple negative breast cancer (TNBC) cells with increased activity of Notch1, as well as CDDP/VPA in the MDA-MB-231 cells with decreased activity of Notch1, yielded an additive interaction, whereas additivity with a tendency towards antagonism was observed for the combination of CDDP/SAHA in MDA-MB-231 cells with the decreased activity of Notch1. Our studies demonstrated that SAHA and VPA might be considered as potential therapeutic agents in combination therapy with CDDP against TNBC with altered Notch1 activity. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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18 pages, 2025 KiB  
Article
Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines
by Paul Noordhuis, Adrianus C. Laan, Kasper van de Born, Richard J. Honeywell and Godefridus J. Peters
Int. J. Mol. Sci. 2019, 20(15), 3619; https://doi.org/10.3390/ijms20153619 - 24 Jul 2019
Cited by 20 | Viewed by 3754
Abstract
Oxaliplatin (OHP) treatment of colorectal cancer (CRC) frequently leads to resistance. OHP resistance was induced in CRC cell lines LoVo-92 and LoVo-Li and a platinum-sensitive ovarian cancer cell line, A2780, and related to cellular platinum accumulation, platinum-DNA adducts, transporter expression, DNA repair genes, [...] Read more.
Oxaliplatin (OHP) treatment of colorectal cancer (CRC) frequently leads to resistance. OHP resistance was induced in CRC cell lines LoVo-92 and LoVo-Li and a platinum-sensitive ovarian cancer cell line, A2780, and related to cellular platinum accumulation, platinum-DNA adducts, transporter expression, DNA repair genes, gene expression arrays, and array-CGH profiling. Pulse (4 h, 4OHP) and continuous exposure (72 h, cOHP) resulted in 4.0 to 7.9-fold and 5.0 to 11.8-fold drug resistance, respectively. Cellular oxaliplatin accumulation and DNA-adduct formation were decreased and related to OCT1-3 and ATP7A expression. Gene expression profiling and pathway analysis showed significantly altered p53 signaling, xenobiotic metabolism, role of BRCA1 in DNA damage response, and aryl hydrocarbon receptor signaling pathways, were related to decreased ALDH1L2, Bax, and BBC3 (PUMA) and increased aldo-keto reductases C1 and C3. The array-CGH profiles showed focal aberrations. In conclusion, OHP resistance was correlated with total platinum accumulation and OCT1-3 expression, decreased proapoptotic, and increased anti-apoptosis and homologous repair genes. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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15 pages, 13377 KiB  
Article
MiR-1208 Increases the Sensitivity to Cisplatin by Targeting TBCK in Renal Cancer Cells
by Eun-Ae Kim, Ji-Hoon Jang, Eon-Gi Sung, In-Hwan Song, Joo-Young Kim and Tae-Jin Lee
Int. J. Mol. Sci. 2019, 20(14), 3540; https://doi.org/10.3390/ijms20143540 - 19 Jul 2019
Cited by 15 | Viewed by 3242
Abstract
MicroRNAs (miRNAs) can be used to target a variety of human malignancies by targeting their oncogenes or tumor suppressor genes. Recent evidence has shown that miRNA-1208 (miR-1208) was rarely expressed in a variety of cancer cells, suggesting the possibility that miR-1208 functions as [...] Read more.
MicroRNAs (miRNAs) can be used to target a variety of human malignancies by targeting their oncogenes or tumor suppressor genes. Recent evidence has shown that miRNA-1208 (miR-1208) was rarely expressed in a variety of cancer cells, suggesting the possibility that miR-1208 functions as a tumor suppressor gene. Herein, ectopic expression of miR-1208 induced the accumulation of sub-G1 populations and the cleavage of procaspase-3 and PARP, which could be prevented by pre-treatment with the pan-caspase inhibitor, Z-VAD. In addition, miR-1208 increased the susceptibility to cisplatin and TRAIL in Caki-1 cells. Luciferase reporter assay results showed that miR-1208 negatively regulates TBC1 domain containing kinase (TBCK) expression by binding to the miR-1208 binding sites in the 3′-untranslated region of TBCK. In addition, miR-1208 specifically repressed TBCK expression at the transcriptional level. In contrast, inhibition of endogenous miR-1208 by anti-miRs resulted in an increase in TBCK expression. Downregulation of TBCK induced by TBCK-specific siRNAs increased susceptibility to cisplatin and TRAIL. These findings suggest that miR-1208 acts as a tumor suppressor and targets TBCK directly, thus possessing great potential for use in renal cancer therapy. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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12 pages, 2110 KiB  
Article
Trifluoperazine, an Antipsychotic Drug, Effectively Reduces Drug Resistance in Cisplatin-Resistant Urothelial Carcinoma Cells via Suppressing Bcl-xL: An In Vitro and In Vivo Study
by Kuan-Lin Kuo, Shing-Hwa Liu, Wei-Chou Lin, Fu-Shun Hsu, Po-Ming Chow, Yu-Wei Chang, Shao-Ping Yang, Chung-Sheng Shi, Chen-Hsun Hsu, Shih-Ming Liao, Hong-Chiang Chang and Kuo-How Huang
Int. J. Mol. Sci. 2019, 20(13), 3218; https://doi.org/10.3390/ijms20133218 - 30 Jun 2019
Cited by 18 | Viewed by 3595
Abstract
Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse. Reduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic agent, has demonstrated antitumor effects on various cancers. This [...] Read more.
Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse. Reduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic agent, has demonstrated antitumor effects on various cancers. This study investigated the efficacy of TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism. Our results revealed that cisplatin-resistant UC cells (T24/R) upregulated the antiapoptotic factor, B-cell lymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells to the cisplatin cytotoxic effect. TFP (10–45 μM) alone elicited dose-dependent cytotoxicity, apoptosis, and G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in T24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with concurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed the T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the T24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and circumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a promising insight to develop a therapeutic strategy for chemoresistant UCs. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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18 pages, 2383 KiB  
Article
Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen †
by Mauro Ravera, Ilaria Zanellato, Elisabetta Gabano, Elena Perin, Beatrice Rangone, Marco Coppola and Domenico Osella
Int. J. Mol. Sci. 2019, 20(12), 3074; https://doi.org/10.3390/ijms20123074 - 24 Jun 2019
Cited by 30 | Viewed by 4758
Abstract
Cisplatin and several non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to act synergistically or at least additively on several tumor cell lines. Dual-action cisplatin-based Pt(IV) combos containing ketoprofen and naproxen offer good antiproliferative performance on a panel of human tumor cell lines, including [...] Read more.
Cisplatin and several non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to act synergistically or at least additively on several tumor cell lines. Dual-action cisplatin-based Pt(IV) combos containing ketoprofen and naproxen offer good antiproliferative performance on a panel of human tumor cell lines, including a malignant pleural mesothelioma (MPM) one, a very chemoresistant tumor. The main reason of the increased activity relies on the enhanced lipophilicity of these Pt(IV) conjugates that in turn promotes increased cellular accumulation. A quick Pt(IV)→Pt(II) reduction generates the active cisplatin metabolite. The NSAID adjuvant action seems to be almost independent from cyclooxygenase-2 (COX-2) expression in the tumor cells under investigation (lung A-549, colon HT-29, HCT 116, SW480, ovarian A2780, and biphasic MPM MSTO-211H), but it seems to rely (at least in part) on the activation of the NSAID activated gene, NAG-1 (a member of the transforming growth factor beta, TGF-β, superfamily), which has been suggested to be involved in NSAID antiproliferative activity. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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24 pages, 6267 KiB  
Article
Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines
by Jan J. Bandolik, Alexandra Hamacher, Christian Schrenk, Robin Weishaupt and Matthias U. Kassack
Int. J. Mol. Sci. 2019, 20(12), 3052; https://doi.org/10.3390/ijms20123052 - 22 Jun 2019
Cited by 32 | Viewed by 3979
Abstract
High grade serous ovarian cancer (HGSOC) is the most common and aggressive ovarian cancer subtype with the worst clinical outcome due to intrinsic or acquired drug resistance. Standard treatment involves platinum compounds. Cancer development and chemoresistance is often associated with an increase in [...] Read more.
High grade serous ovarian cancer (HGSOC) is the most common and aggressive ovarian cancer subtype with the worst clinical outcome due to intrinsic or acquired drug resistance. Standard treatment involves platinum compounds. Cancer development and chemoresistance is often associated with an increase in histone deacetylase (HDAC) activity. The purpose of this study was to examine the potential of HDAC inhibitors (HDACi) to increase platinum potency in HGSOC. Four HGSOC cell lines with different cisplatin sensitivity were treated with combinations of cisplatin and entinostat (class I HDACi), panobinostat (pan-HDACi), or nexturastat A (class IIb HDACi), respectively. Inhibition of class I HDACs by entinostat turned out superior in increasing cisplatin potency than pan-HDAC inhibition in cell viability assays (MTT), apoptosis induction (subG1), and caspase 3/7 activation. Entinostat was synergistic with cisplatin in all cell lines in MTT and caspase activation assays. MTT assays gave combination indices (CI values) < 0.9 indicating synergism. The effect of HDAC inhibitors could be attributed to the upregulation of pro-apoptotic genes (CDNK1A, APAF1, PUMA, BAK1) and downregulation of survivin. In conclusion, the combination of entinostat and cisplatin is synergistic in HGSOC and could be an effective strategy for the treatment of aggressive ovarian cancer. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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10 pages, 12923 KiB  
Article
Upregulation of MDR- and EMT-Related Molecules in Cisplatin-Resistant Human Oral Squamous Cell Carcinoma Cell Lines
by Hyeong Sim Choi, Young-Kyun Kim and Pil-Young Yun
Int. J. Mol. Sci. 2019, 20(12), 3034; https://doi.org/10.3390/ijms20123034 - 21 Jun 2019
Cited by 26 | Viewed by 3488
Abstract
Cisplatin is one of the major drugs used in oral cancer treatments, but its usage can be limited by acquired drug resistance. In this study, we established three cisplatin-resistant oral squamous cell carcinoma (OSCC) cell lines and characterized them using cell viability assays, [...] Read more.
Cisplatin is one of the major drugs used in oral cancer treatments, but its usage can be limited by acquired drug resistance. In this study, we established three cisplatin-resistant oral squamous cell carcinoma (OSCC) cell lines and characterized them using cell viability assays, qPCR, Western blotting, FACS, immunofluorescence, and wound healing assays. Three OSCC cell lines (YD-8, YD-9, and YD-38) underwent long-term exposure to cisplatin, eventually acquiring resistance to the drug, which was confirmed by an MTT assay. In these three newly established cell lines (YD-8/CIS, YD-9/CIS, and YD-38/CIS), overexpression of multidrug resistance (MDR)-related genes was detected by qPCR and Western blotting. The cell lines displayed an increase in the functional activities of breast cancer resistance protein (BCRP) and multidrug resistance protein1 (MDR1) by rhodamine 123 and bodipy FL prazosin accumulation assays. Moreover, the cisplatin-resistant cells underwent morphological changes, from round to spindle-shaped, increased expression of epithelial-to-mesenchymal transition (EMT)-related molecules such as N-cadherin, and showed increased cell migration when compared with the parental cell lines. These results suggest that these newly established cell lines have acquired drug resistance and EMT induction. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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13 pages, 2174 KiB  
Article
Promotion of Cell Death in Cisplatin-Resistant Ovarian Cancer Cells through KDM1B-DCLRE1B Modulation
by Yeon Kyu Lee, Jinyeong Lim, So Young Yoon, Jong Cheon Joo, Soo Jung Park and Yoon Jung Park
Int. J. Mol. Sci. 2019, 20(10), 2443; https://doi.org/10.3390/ijms20102443 - 17 May 2019
Cited by 17 | Viewed by 4024
Abstract
Ovarian cancer is the gynecological malignancy with the poorest prognosis, in part due to its high incidence of recurrence. Platinum agents are widely used as a first-line treatment against ovarian cancer. Recurrent tumors, however, frequently demonstrate acquired chemo-resistance to platinum agent toxicity. To [...] Read more.
Ovarian cancer is the gynecological malignancy with the poorest prognosis, in part due to its high incidence of recurrence. Platinum agents are widely used as a first-line treatment against ovarian cancer. Recurrent tumors, however, frequently demonstrate acquired chemo-resistance to platinum agent toxicity. To improve chemo-sensitivity, combination chemotherapy regimens have been investigated. This study examined anti-tumor effects and molecular mechanisms of cytotoxicity of Oldenlandia diffusa (OD) extracts on ovarian cancer cells, in particular, cells resistant to cisplatin. Six ovarian cancer cells including A2780 and cisplatin-resistant A2780 (A2780cis) as representative cell models were used. OD was extracted with water (WOD) or 50% methanol (MOD). MOD significantly induced cell death in both cisplatin-sensitive cells and cisplatin-resistant cells. The combination treatment of MOD with cisplatin reduced viability in A2780cis cells more effectively than treatment with cisplatin alone. MOD in A2780cis cells resulted in downregulation of the epigenetic modulator KDM1B and the DNA repair gene DCLRE1B. Transcriptional suppression of KDM1B and DCLRE1B induced cisplatin sensitivity. Knockdown of KDM1B led to downregulation of DCLRE1B expression, suggesting that DCLRE1B was a KDM1B downstream target. Taken together, OD extract effectively promoted cell death in cisplatin-resistant ovarian cancer cells under cisplatin treatment through modulating KDM1B and DCLRE1B. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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16 pages, 5373 KiB  
Article
Cisplatin Synergistically Enhances Antitumor Potency of Conditionally Replicating Adenovirus via p53 Dependent or Independent Pathways in Human Lung Carcinoma
by Sakhawat Ali, Muhammad Tahir, Aamir Ali Khan, Xue Chai Chen, Ma Ling and Yinghui Huang
Int. J. Mol. Sci. 2019, 20(5), 1125; https://doi.org/10.3390/ijms20051125 - 05 Mar 2019
Cited by 15 | Viewed by 4984
Abstract
Cisplatin is ranked as one of the most powerful and commonly prescribed anti-tumor chemotherapeutic agents which improve survival in many solid tumors including non-small cell lung cancer. However, the treatment of advanced lung cancer is restricted due to chemotherapy resistance. Here, we developed [...] Read more.
Cisplatin is ranked as one of the most powerful and commonly prescribed anti-tumor chemotherapeutic agents which improve survival in many solid tumors including non-small cell lung cancer. However, the treatment of advanced lung cancer is restricted due to chemotherapy resistance. Here, we developed and investigated survivin promoter regulating conditionally replicating adenovirus (CRAd) for its anti-tumor potential alone or in combination with cisplatin in two lung cancer cells, H23, H2126, and their resistant cells, H23/CPR, H2126/CPR. To measure the expression of genes which regulate resistance, adenoviral transduction, metastasis, and apoptosis in cancer cells, RT-PCR and Western blotting were performed. The anti-tumor efficacy of the treatments was evaluated through flow cytometry, MTT and transwell assays. This study demonstrated that co-treatment with cisplatin and CRAd exerts synergistic anti-tumor effects on chemotherapy sensitive lung cancer cells and monotherapy of CRAd could be a practical approach to deal with chemotherapy resistance. Combined treatment induced stronger apoptosis by suppressing the anti-apoptotic molecule Bcl-2, and reversed epithelial to mesenchymal transition. In conclusion, cisplatin synergistically increased the tumor-killing of CRAd by (1) increasing CRAd transduction via enhanced CAR expression and (2) increasing p53 dependent or independent apoptosis of lung cancer cell lines. Also, CRAd alone proved to be a very efficient anti-tumor agent in cancer cells resistant to cisplatin owing to upregulated CAR levels. In an exciting outcome, we have revealed novel therapeutic opportunities to exploit intrinsic and acquired resistance to enhance the therapeutic index of anti-tumor treatment in lung cancer. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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19 pages, 567 KiB  
Review
Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies
by Elena Conte, Elena Bresciani, Laura Rizzi, Ornella Cappellari, Annamaria De Luca, Antonio Torsello and Antonella Liantonio
Int. J. Mol. Sci. 2020, 21(4), 1242; https://doi.org/10.3390/ijms21041242 - 13 Feb 2020
Cited by 71 | Viewed by 6301
Abstract
Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. [...] Read more.
Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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10 pages, 1604 KiB  
Review
The Pentose Phosphate Pathway and Its Involvement in Cisplatin Resistance
by Isabella Giacomini, Eugenio Ragazzi, Gianfranco Pasut and Monica Montopoli
Int. J. Mol. Sci. 2020, 21(3), 937; https://doi.org/10.3390/ijms21030937 - 31 Jan 2020
Cited by 83 | Viewed by 6986
Abstract
Cisplatin is the first-line treatment for different types of solid tumors, such as ovarian, testicular, bladder, cervical, head and neck, lung, and esophageal cancers. The main problem related to its clinical use is the onset of drug resistance. In the last decades, among [...] Read more.
Cisplatin is the first-line treatment for different types of solid tumors, such as ovarian, testicular, bladder, cervical, head and neck, lung, and esophageal cancers. The main problem related to its clinical use is the onset of drug resistance. In the last decades, among the studied molecular mechanisms of cisplatin resistance, metabolic reprogramming has emerged as a possible one. This review focuses on the pentose phosphate pathway (PPP) playing a pivotal role in maintaining the high cell proliferation rate and representing an advantage for cancer cells. In particular, the oxidative branch of PPP plays a role in oxidative stress and seems to be involved in cisplatin resistance. In light of these considerations, it has been demonstrated that overexpression and higher enzymatic activity of different enzymes of both oxidative and non-oxidative branches (such as glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and transketolase) increase cisplatin resistance, and their silencing or combined treatment with cisplatin could restore cisplatin sensitivity. Moreover, drug delivery systems loaded with both PPP inhibitors and cisplatin give the possibility of reaching cancer cells selectively. In conclusion, targeting PPP is becoming a strategy to overcome cisplatin resistance; however, further studies are required to better understand the mechanisms. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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21 pages, 861 KiB  
Review
New Insights into Mechanisms of Cisplatin Resistance: From Tumor Cell to Microenvironment
by Shang-Hung Chen and Jang-Yang Chang
Int. J. Mol. Sci. 2019, 20(17), 4136; https://doi.org/10.3390/ijms20174136 - 24 Aug 2019
Cited by 260 | Viewed by 14231
Abstract
Although cisplatin has been a pivotal chemotherapy drug in treating patients with various types of cancer for decades, drug resistance has been a major clinical impediment. In general, cisplatin exerts cytotoxic effects in tumor cells mainly through the generation of DNA-platinum adducts and [...] Read more.
Although cisplatin has been a pivotal chemotherapy drug in treating patients with various types of cancer for decades, drug resistance has been a major clinical impediment. In general, cisplatin exerts cytotoxic effects in tumor cells mainly through the generation of DNA-platinum adducts and subsequent DNA damage response. Accordingly, considerable effort has been devoted to clarify the resistance mechanisms inside tumor cells, such as decreased drug accumulation, enhanced detoxification activity, promotion of DNA repair capacity, and inactivated cell death signaling. However, recent advances in high-throughput techniques, cell culture platforms, animal models, and analytic methods have also demonstrated that the tumor microenvironment plays a key role in the development of cisplatin resistance. Recent clinical successes in combination treatments with cisplatin and novel agents targeting components in the tumor microenvironment, such as angiogenesis and immune cells, have also supported the therapeutic value of these components in cisplatin resistance. In this review, we summarize resistance mechanisms with respect to a single tumor cell and crucial components in the tumor microenvironment, particularly focusing on favorable results from clinical studies. By compiling emerging evidence from preclinical and clinical studies, this review may provide insights into the development of a novel approach to overcome cisplatin resistance. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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15 pages, 554 KiB  
Review
Platinum Salts in Patients with Breast Cancer: A Focus on Predictive Factors
by Mattia Garutti, Giacomo Pelizzari, Michele Bartoletti, Matilde Clarissa Malfatti, Lorenzo Gerratana, Gianluca Tell and Fabio Puglisi
Int. J. Mol. Sci. 2019, 20(14), 3390; https://doi.org/10.3390/ijms20143390 - 10 Jul 2019
Cited by 50 | Viewed by 6078
Abstract
Breast cancer (BC) is the most frequent oncologic cause of death among women and the improvement of its treatments is compelling. Platinum salts (e.g., carboplatin, cisplatin, and oxaliplatin) are old drugs still used to treat BC, especially the triple-negative subgroup. However, only a [...] Read more.
Breast cancer (BC) is the most frequent oncologic cause of death among women and the improvement of its treatments is compelling. Platinum salts (e.g., carboplatin, cisplatin, and oxaliplatin) are old drugs still used to treat BC, especially the triple-negative subgroup. However, only a subset of patients see a concrete benefit from these drugs, raising the question of how to select them properly. Therefore, predictive biomarkers for platinum salts in BC still represent an unmet clinical need. Here, we review clinical and preclinical works in order to summarize the current evidence about predictive or putative platinum salt biomarkers in BC. The association between BRCA1/2 gene mutations and platinum sensitivity has been largely described. However, beyond the mutations of these two genes, several other proteins belonging to the homologous recombination pathways have been linked to platinum response, defining the concept of BRCAness. Several works, here reviewed, have tried to capture BRCAness through different strategies, such as homologous recombination deficiency (HRD) score and genetic signatures. Moreover, p53 and its family members (p63 and p73) might also be used as predictors of platinum response. Finally, we describe the mounting preclinical evidence regarding base excision repair deficiency as a possible new platinum biomarker. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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17 pages, 498 KiB  
Review
Mitochondrial Involvement in Cisplatin Resistance
by Veronica Cocetta, Eugenio Ragazzi and Monica Montopoli
Int. J. Mol. Sci. 2019, 20(14), 3384; https://doi.org/10.3390/ijms20143384 - 10 Jul 2019
Cited by 82 | Viewed by 6999
Abstract
Cisplatin is one of the worldwide anticancer drugs and, despite its toxicity and frequent recurrence of resistance phenomena, it still remains the only therapeutic option for several tumors. Circumventing cisplatin resistance remains, therefore, a major goal for clinical therapy and represents a challenge [...] Read more.
Cisplatin is one of the worldwide anticancer drugs and, despite its toxicity and frequent recurrence of resistance phenomena, it still remains the only therapeutic option for several tumors. Circumventing cisplatin resistance remains, therefore, a major goal for clinical therapy and represents a challenge for scientific research. Recent studies have brought to light the fundamental role of mitochondria in onset, progression, and metastasis of cancer, as well as its importance in the resistance to chemotherapy. The aim of this review is to give an overview of the current knowledge about the implication of mitochondria in cisplatin resistance and on the recent development in this research field. Recent studies have highlighted the role of mitochondrial DNA alterations in onset of resistance phenomena, being related both to redox balance alterations and to signal crosstalk with the nucleus, allowing a rewiring of cell metabolism. Moreover, an important role of the mitochondrial dynamics in the adaptation mechanism of cancer cells to challenging environment has been revealed. Giving bioenergetic plasticity to tumor cells, mitochondria allow cells to evade death pathways in stressful conditions, including chemotherapy. So far, even if the central role of mitochondria is recognized, little is known about the specific mechanisms implicated in the resistance. Nevertheless, mitochondria appear to be promising pharmacological targets for overcoming cisplatin resistance, but further studies are necessary. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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25 pages, 540 KiB  
Review
Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury
by Sara J. Holditch, Carolyn N. Brown, Andrew M. Lombardi, Khoa N. Nguyen and Charles L. Edelstein
Int. J. Mol. Sci. 2019, 20(12), 3011; https://doi.org/10.3390/ijms20123011 - 20 Jun 2019
Cited by 219 | Viewed by 10831
Abstract
Cisplatin is a widely used chemotherapeutic agent used to treat solid tumours, such as ovarian, head and neck, and testicular germ cell. A known complication of cisplatin administration is acute kidney injury (AKI). The development of effective tumour interventions with reduced nephrotoxicity relies [...] Read more.
Cisplatin is a widely used chemotherapeutic agent used to treat solid tumours, such as ovarian, head and neck, and testicular germ cell. A known complication of cisplatin administration is acute kidney injury (AKI). The development of effective tumour interventions with reduced nephrotoxicity relies heavily on understanding the molecular pathophysiology of cisplatin-induced AKI. Rodent models have provided mechanistic insight into the pathophysiology of cisplatin-induced AKI. In the subsequent review, we provide a detailed discussion of recent advances in the cisplatin-induced AKI phenotype, principal mechanistic findings of injury and therapy, and pre-clinical use of AKI rodent models. Cisplatin-induced AKI murine models faithfully develop gross manifestations of clinical AKI such as decreased kidney function, increased expression of tubular injury biomarkers, and tubular injury evident by histology. Pathways involved in AKI include apoptosis, necrosis, inflammation, and increased oxidative stress, ultimately providing a translational platform for testing the therapeutic efficacy of potential interventions. This review provides a discussion of the foundation laid by cisplatin-induced AKI rodent models for our current understanding of AKI molecular pathophysiology. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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12 pages, 747 KiB  
Review
Inhaled Cisplatin for NSCLC: Facts and Results
by Christoforos Kosmidis, Konstantinos Sapalidis, Paul Zarogoulidis, Chrysanthi Sardeli, Charilaos Koulouris, Dimitrios Giannakidis, Efstathios Pavlidis, Athanasios Katsaounis, Nikolaos Michalopoulos, Stylianos Mantalobas, Georgios Koimtzis, Vyron Alexandrou, Theodora Tsiouda, Aikaterini Amaniti and Issak Kesisoglou
Int. J. Mol. Sci. 2019, 20(8), 2005; https://doi.org/10.3390/ijms20082005 - 24 Apr 2019
Cited by 17 | Viewed by 3834
Abstract
Although we have new diagnostic tools for non-small cell lung cancer, diagnosis is still made in advanced stages of the disease. However, novel treatments are being introduced in the market and new ones are being developed. Targeted therapies and immunotherapy have brought about [...] Read more.
Although we have new diagnostic tools for non-small cell lung cancer, diagnosis is still made in advanced stages of the disease. However, novel treatments are being introduced in the market and new ones are being developed. Targeted therapies and immunotherapy have brought about a bloom in the treatment of non-small cell lung cancer. Still we have to find ways to administer drugs in a more efficient and safe method. In the current review, we will focus on the administration of inhaled cisplatin based on published data. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action)
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