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Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0
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Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0

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 (30 November 2020) | Viewed by 33820

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

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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,

Due to the great success of the first Edition “Cisplatin in Cancer Therapy: Molecular Mechanisms of Action”, in which approximately 20 papers were published (and which can be accessed by clicking: https://www.mdpi.com/journal/ijms/special_issues/cisplatin_cancer_therapy), a second Edition of this Special Issue is launched.

Although it has been 40 years since the FDA approved the use of cisplatin in the treatment of cancer (an event celebrated at Michigan State University), 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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Related Special Issue

Published Papers (7 papers)

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Research

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17 pages, 1389 KiB  
Article
Effect of Cilastatin on Cisplatin-Induced Nephrotoxicity in Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy
by Matilde Zaballos, Mercedes Power, María Iluminada Canal-Alonso, María Ángeles González-Nicolás, Wenceslao Vasquez-Jimenez, Pablo Lozano-Lominchar, Pilar Cabrerizo-Torrente, Natividad Palencia-García, Susana Gago-Quiroga, María Dolores Ginel-Feito, Consuelo Jiménez, Alberto Lázaro and Luis González-Bayón
Int. J. Mol. Sci. 2021, 22(3), 1239; https://doi.org/10.3390/ijms22031239 - 27 Jan 2021
Cited by 15 | Viewed by 3537
Abstract
Cisplatin is one of the most widely used chemotherapeutic agents in oncology, although its nephrotoxicity limits application and dosage. We present the results of a clinical study on prophylaxis of cisplatin-induced nephrotoxicity in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal intraoperative [...] Read more.
Cisplatin is one of the most widely used chemotherapeutic agents in oncology, although its nephrotoxicity limits application and dosage. We present the results of a clinical study on prophylaxis of cisplatin-induced nephrotoxicity in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC-cisplatin). Prophylaxis was with imipenem/cilastatin. Cilastatin is a selective inhibitor of renal dehydropeptidase I in the proximal renal tubule cells that can reduce the nephrotoxicity of cisplatin. Unfortunately, cilastatin is not currently marketed alone, and can only be administered in combination with imipenem. The study has a retrospective part that serves as a control (n = 99 patients receiving standard surgical prophylaxis) and a prospective part with imipenem/cilastatin prophylaxis corresponding to the study group (n = 85 patients). In both groups, we collected specific data on preoperative risk factors of renal damage, fluid management, hemodynamic control, and urine volume during surgery (including the hyperthermic chemotherapy perfusion), as well as data on hemodynamic and renal function during the first seven days after surgery. The main finding of the study is that cilastatin may exert a nephroprotective effect in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal cisplatin perfusion. Creatinine values remained lower than in the control group (ANOVA test, p = 0.037). This translates into easier management of these patients in the postoperative period, with significantly shorter intensive care unit (ICU) and hospital stay. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0)
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12 pages, 2185 KiB  
Article
Increased FOXM1 Expression by Cisplatin Inhibits Paclitaxel-Related Apoptosis in Cisplatin-Resistant Human Oral Squamous Cell Carcinoma (OSCC) Cell Lines
by Hyeong Sim Choi, Young-Kyun Kim, Kyung-Gyun Hwang and Pil-Young Yun
Int. J. Mol. Sci. 2020, 21(23), 8897; https://doi.org/10.3390/ijms21238897 - 24 Nov 2020
Cited by 13 | Viewed by 2447
Abstract
Cisplatin and paclitaxel are commonly used to treat oral cancer, but their use is often limited because of acquired drug resistance. Here, we tested the effects of combined cisplatin and paclitaxel on three parental (YD-8, YD-9, and YD-38) and three cisplatin-resistant (YD-8/CIS, YD-9/CIS, [...] Read more.
Cisplatin and paclitaxel are commonly used to treat oral cancer, but their use is often limited because of acquired drug resistance. Here, we tested the effects of combined cisplatin and paclitaxel on three parental (YD-8, YD-9, and YD-38) and three cisplatin-resistant (YD-8/CIS, YD-9/CIS, and YD-38/CIS) oral squamous cell carcinoma (OSCC) cell lines using cell proliferation assays and combination index analysis. We detected forkhead box protein M1 (FOXM1) mRNA and protein expression via real-time qPCR and Western blot assays. Cell death of the cisplatin-resistant cell lines in response to these drugs with or without a FOXM1 inhibitor (forkhead domain inhibitory compound 6) was then measured by propidium iodide staining and TdT dUTP nick end labeling (TUNEL) assays. In all six OSCC cell lines, cell growth was more inhibited by paclitaxel alone than combination therapy. Cisplatin-induced overexpression of FOXM1 showed the same trend only in cisplatin-resistant cell lines, indicating that it was associated with inhibition of paclitaxel-related apoptosis. In summary, these results suggest that, in three cisplatin-resistant cell lines, the combination of cisplatin and paclitaxel had an antagonistic effect, likely because cisplatin blocks paclitaxel-induced apoptosis. Cisplatin-induced FOXM1 overexpression may explain the failure of this combination. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0)
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38 pages, 1329 KiB  
Article
Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models
by Safiah Ibrahim Althurwi, Jun Q. Yu, Philip Beale and Fazlul Huq
Int. J. Mol. Sci. 2020, 21(20), 7500; https://doi.org/10.3390/ijms21207500 - 12 Oct 2020
Cited by 9 | Viewed by 3863
Abstract
In the present study, cisplatin, artemisinin, and oleanolic acid were evaluated alone, and in combination, on human ovarian A2780, A2780ZD0473R, and A2780cisR cancer cell lines, with the aim of overcoming cisplatin resistance and side effects. Cytotoxicity was assessed by MTT [...] Read more.
In the present study, cisplatin, artemisinin, and oleanolic acid were evaluated alone, and in combination, on human ovarian A2780, A2780ZD0473R, and A2780cisR cancer cell lines, with the aim of overcoming cisplatin resistance and side effects. Cytotoxicity was assessed by MTT reduction assay. Combination index (CI) values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. Moreover, 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780cisR cells. The proteins were found to play critical roles in cell cycle regulation, metabolism, and biosynthetic processes and drug resistance and detoxification. Results indicate that appropriately sequenced combinations of cisplatin with artemisinin (ART) and oleanolic acid (OA) may provide a means to reduce side effects and circumvent platinum resistance. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0)
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21 pages, 5640 KiB  
Article
Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics
by Sarah Schoch, Sabine Gajewski, Jana Rothfuß, Andrea Hartwig and Beate Köberle
Int. J. Mol. Sci. 2020, 21(18), 6928; https://doi.org/10.3390/ijms21186928 - 21 Sep 2020
Cited by 42 | Viewed by 7522
Abstract
Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher [...] Read more.
Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death. Gene expression profiling displayed modulation of genes related to DNA damage response/repair, cell cycle regulation and apoptosis which was more pronounced upon oxaliplatin treatment. Furthermore, repression of specific DNA repair genes was restricted to oxaliplatin. Transcriptional level observations were further analyzed on the functional level. Uptake studies revealed low intracellular platinum accumulation and DNA platination upon carboplatin treatment. Removal of overall DNA platination was comparable for the three drugs. However, no processing of oxaliplatin-induced interstrand crosslinks was observed. Cisplatin and carboplatin influenced cell cycle distribution comparably, while oxaliplatin had no effect. Altogether, we found a similar mode of action for cisplatin and carboplatin, while the activity of oxaliplatin appeared to differ. This might be clinically relevant as due to the difference in mode of action oxaliplatin could be active in tumors which show resistance towards cisplatin and carboplatin. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0)
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16 pages, 2048 KiB  
Article
Flavonoids Restore Platinum Drug Sensitivity to Ovarian Carcinoma Cells in a Phospho-ERK1/2-Dependent Fashion
by Yifat Koren Carmi, Hatem Mahmoud, Hazem Khamaisi, Rina Adawi, Jacob Gopas and Jamal Mahajna
Int. J. Mol. Sci. 2020, 21(18), 6533; https://doi.org/10.3390/ijms21186533 - 7 Sep 2020
Cited by 14 | Viewed by 3227
Abstract
Ovarian cancer (OC) is the second most common type of gynecological malignancy; it has poor survival rates and is frequently (>75%) diagnosed at an advanced stage. Platinum-based chemotherapy, with, e.g., carboplatin, is the standard of care for OC, but toxicity and acquired resistance [...] Read more.
Ovarian cancer (OC) is the second most common type of gynecological malignancy; it has poor survival rates and is frequently (>75%) diagnosed at an advanced stage. Platinum-based chemotherapy, with, e.g., carboplatin, is the standard of care for OC, but toxicity and acquired resistance to therapy have proven challenging. Despite advances in OC diagnosis and treatment, approximately 85% of patients will experience relapse, mainly due to chemoresistance. The latter is attributed to alterations in the cancer cells and is also mediated by tumor microenvironment (TME). Recently, we reported the synthesis of a platinum (IV) prodrug that exhibits equal potency toward platinum-sensitive and resistant OC cell lines. Here, we investigated the effect of TME on platinum sensitivity. Co-culture of OC cells with murine or human mesenchymal stem cells (MS-5 and HS-5, respectively) rendered them resistant to chemotherapeutic agents, including platinum, paclitaxel and colchicine. Platinum resistance was also conferred by co-culture with differentiated murine adipocyte progenitor cells. Exposure of OC cells to chemotherapeutic agents resulted in activation of phospho-ERK1/2. Co-culture with MS-5, which conferred drug resistance, was accompanied by blockage of phospho-ERK1/2 activation. The flavonoids fisetin and quercetin were active in restoring ERK phosphorylation, as well as sensitivity to platinum compounds. Exposure of OC cells to cobimetinib—a MEK1 inhibitor that also inhibits extracellular signal-regulated kinase (ERK) phosphorylation—which resulted in reduced sensitivity to the platinum compound. This suggests that ERK activity is involved in mediating the function of flavonoids in restoring platinum sensitivity to OC co-cultured with cellular components of the TME. Our data show the potential of combining flavonoids with standard therapy to restore drug sensitivity to OC cells and overcome TME-mediated platinum drug resistance. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0)
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15 pages, 3425 KiB  
Article
HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3
by Sang Ah Yi, Go Woon Kim, Jung Yoo, Jeung-Whan Han and So Hee Kwon
Int. J. Mol. Sci. 2020, 21(17), 5976; https://doi.org/10.3390/ijms21175976 - 19 Aug 2020
Cited by 15 | Viewed by 3266
Abstract
Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby [...] Read more.
Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby enhancing the stability of tumor suppressor p53 specifically in cervical cancer cells. As a follow-up study of our previous findings, here we have identified that the pharmacological substances, leptomycin B and doxorubicin, can improve the sensitivity of cervical cancer cells to cisplatin inducing HP1γ-mediated elevation of p53. Leptomycin B, which inhibits the nuclear export of HP1γ, increased cisplatin-dependent apoptosis induction by promoting the activation of p53 signaling. We also found that doxorubicin, which induces the DNA damage response, promotes HP1γ-mediated silencing of UBE2L3 and increases p53 stability. These effects resulted from the nuclear translocation and binding of HP1γ on the UBE2L3 promoter. Doxorubicin sensitized the cisplatin-resistant cervical cancer cells, enhancing their p53 levels and rate of apoptosis when administered together with cisplatin. Our findings reveal a therapeutic strategy to target a specific molecular pathway that contributes to p53 degradation for the treatment of patients with cervical cancer, particularly with cisplatin resistance. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0)
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Review

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46 pages, 1302 KiB  
Review
Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance
by Milad Ashrafizadeh, Ali Zarrabi, Kiavash Hushmandi, Mahshad Kalantari, Reza Mohammadinejad, Tahereh Javaheri and Gautam Sethi
Int. J. Mol. Sci. 2020, 21(11), 4002; https://doi.org/10.3390/ijms21114002 - 3 Jun 2020
Cited by 179 | Viewed by 8681
Abstract
Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP [...] Read more.
Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial–mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell–cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0)
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