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Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 4.0
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Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 4.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 March 2024) | Viewed by 7366

Special Issue Editors

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
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. Nicola Margiotta

E-Mail Website
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

Special Issue Information

Dear Colleagues,

Due to the great success of the first, second and third edition of “Cisplatin in Cancer Therapy: Molecular Mechanisms of Action”, in which approximately 20, 7 and 9 papers, respectively, were published (and which can be accessed at https://www.mdpi.com/journal/ijms/special_issues/cisplatin_cancer_therapy), a fourth edition of this Special Issue has been launched.

Although it has been 45 years since the FDA approval of cisplatin for the treatment of cancer, its mechanism of action has not yet been fully elucidated. The mechanism of action of cisplatin is known so far to include four key steps: (1) cellular uptake, (2) activation by aquation, (3) DNA binding, and (4) the processing of DNA lesions, which may alter both DNA transcription and RNA replication, 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 related 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 explore in detail the nature of the intracellular pathways affected by the platinum–DNA adducts, which are responsible for developing resistance or a differential response in tumors to platinum drugs (i.e., cisplatin and oxaliplatin have different activities toward colorectal cancer). 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 these uncertainties regarding the mechanism of action of cisplatin can be elucidated within five years, in time to celebrate the 50th anniversary of the FDA’s approval of cisplatin.

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cisplatin
  • antitumor platinum agents
  • alkylating drugs
  • platinum–DNA adducts
  • DNA–repair
  • mechanisms
  • apoptosis
  • carboplatin
  • oxaliplatin

Published Papers (5 papers)

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Editorial

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5 pages, 202 KiB  
Editorial
Special Issue “Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0”
by Valentina Gandin, James D. Hoeschele and Nicola Margiotta
Int. J. Mol. Sci. 2023, 24(9), 7917; https://doi.org/10.3390/ijms24097917 - 27 Apr 2023
Cited by 5 | Viewed by 1600
Abstract
The year 2023 marks the 45th year since FDA approval of cisplatin as an anticancer drug, and, at present, it is widely used against a spectrum of human tumors, including early-stage ovarian cancer, non-small cell lung cancer (typically developed by smokers), head and [...] Read more.
The year 2023 marks the 45th year since FDA approval of cisplatin as an anticancer drug, and, at present, it is widely used against a spectrum of human tumors, including early-stage ovarian cancer, non-small cell lung cancer (typically developed by smokers), head and neck, and advanced bladder cancer [...] Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 4.0)

Research

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16 pages, 3043 KiB  
Article
Mechanistic Protective Effect of Cilostazol in Cisplatin-Induced Testicular Damage via Regulation of Oxidative Stress and TNF-α/NF-κB/Caspase-3 Pathways
by Eman M. Othman, Heba A. Habib, Mahmoud E. Zahran, Amr Amin and Gehan H. Heeba
Int. J. Mol. Sci. 2023, 24(16), 12651; https://doi.org/10.3390/ijms241612651 - 10 Aug 2023
Cited by 1 | Viewed by 1255
Abstract
Despite being a potent anticancer drug, cisplatin has limited applicability due to its adverse effects, such as testicular damage. Consequently, reducing its toxicity becomes necessary. In this study, a selective phosphodiesterase-3 inhibitor, cilostazol, which is used to treat intermittent claudication, was examined for [...] Read more.
Despite being a potent anticancer drug, cisplatin has limited applicability due to its adverse effects, such as testicular damage. Consequently, reducing its toxicity becomes necessary. In this study, a selective phosphodiesterase-3 inhibitor, cilostazol, which is used to treat intermittent claudication, was examined for its ability to abrogate cisplatin-induced testicular toxicity. Its ameliorative effect was compared to that of two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Cisplatin-treated rats showed a significant decrease in sperm number and motility, serum testosterone, and testicular glutathione levels, as well as a significant elevation in malondialdehyde, total nitrite levels, and the protein expression of tumor necrosis factor-alpha, nuclear factor-kappa β, and caspase-3. These outcomes were confirmed by marked testicular architecture deterioration. Contrary to this, cilostazol, in a dose-dependent manner, showed potential protection against testicular toxicity, reversed the disrupted testicular function, and improved histological alterations through rebalancing of oxidative stress, inflammation, and apoptosis. In addition, cilostazol exerted a more pronounced protective effect in comparison to tadalafil and pentoxifylline. In conclusion, cilostazol ameliorates cisplatin-induced testicular impairment through alteration of oxidative stress, inflammation, and apoptotic pathways, offering a promising treatment for cisplatin-induced testicular damage. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 4.0)
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16 pages, 3791 KiB  
Article
Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines
by James Patrick Heiserman, Zenab Minhas, Elahe Nikpayam and Dong-Joo Cheon
Int. J. Mol. Sci. 2023, 24(16), 12638; https://doi.org/10.3390/ijms241612638 - 10 Aug 2023
Viewed by 1356
Abstract
Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines [...] Read more.
Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors in vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin’s cytotoxic effect. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 4.0)
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Review

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23 pages, 1882 KiB  
Review
Role of Epigenetics for the Efficacy of Cisplatin
by Tatjana Lumpp, Sandra Stößer, Franziska Fischer, Andrea Hartwig and Beate Köberle
Int. J. Mol. Sci. 2024, 25(2), 1130; https://doi.org/10.3390/ijms25021130 - 17 Jan 2024
Cited by 1 | Viewed by 1239
Abstract
The clinical utility of the chemotherapeutic agent cisplatin is restricted by cancer drug resistance, which is either intrinsic to the tumor or acquired during therapy. Epigenetics is increasingly recognized as a factor contributing to cisplatin resistance and hence influences drug efficacy and clinical [...] Read more.
The clinical utility of the chemotherapeutic agent cisplatin is restricted by cancer drug resistance, which is either intrinsic to the tumor or acquired during therapy. Epigenetics is increasingly recognized as a factor contributing to cisplatin resistance and hence influences drug efficacy and clinical outcomes. In particular, epigenetics regulates gene expression without changing the DNA sequence. Common types of epigenetic modifications linked to chemoresistance are DNA methylation, histone modification, and non-coding RNAs. This review provides an overview of the current findings of various epigenetic modifications related to cisplatin efficacy in cell lines in vitro and in clinical tumor samples. Furthermore, it discusses whether epigenetic alterations might be used as predictors of the platinum agent response in order to prevent avoidable side effects in patients with resistant malignancies. In addition, epigenetic targeting therapies are described as a possible strategy to render cancer cells more susceptible to platinum drugs. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 4.0)
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19 pages, 1009 KiB  
Review
Tumor Cells Transmit Drug Resistance via Cisplatin-Induced Extracellular Vesicles
by Jian Wang, Qingqing Liu, Yuanxin Zhao, Jiaying Fu and Jing Su
Int. J. Mol. Sci. 2023, 24(15), 12347; https://doi.org/10.3390/ijms241512347 - 2 Aug 2023
Cited by 3 | Viewed by 1402
Abstract
Cisplatin is a first-line clinical agent used for treating solid tumors. Cisplatin damages the DNA of tumor cells and induces the production of high levels of reactive oxygen species to achieve tumor killing. Tumor cells have evolved several ways to tolerate this damage. [...] Read more.
Cisplatin is a first-line clinical agent used for treating solid tumors. Cisplatin damages the DNA of tumor cells and induces the production of high levels of reactive oxygen species to achieve tumor killing. Tumor cells have evolved several ways to tolerate this damage. Extracellular vesicles (EVs) are an important mode of information transfer in tumor cells. EVs can be substantially activated under cisplatin treatment and mediate different responses of tumor cells under cisplatin treatment depending on their different cargoes. However, the mechanism of action of tumor-cell-derived EVs under cisplatin treatment and their potential cargoes are still unclear. This review considers recent advances in cisplatin-induced release of EVs from tumor cells, with the expectation of providing a new understanding of the mechanisms of cisplatin treatment and drug resistance, as well as strategies for the combined use of cisplatin and other drugs. Full article
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 4.0)
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