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Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0

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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 April 2022) | Viewed by 32381

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Dr. Nicola Margiotta

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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
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Dr. James D. Hoeschele

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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
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Dr. Valentina Gandin

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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 and second Edition “Cisplatin in Cancer Therapy: Molecular Mechanisms of Action”, in which approximately 20 and 7 papers, respectively, were published (and which can be accessed by clicking: https://www.mdpi.com/journal/ijms/special_issues/cisplatin_cancer_therapy), a THIRD 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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Cisplatin in Cancer Therapy: Molecular Mechanisms of Action in International Journal of Molecular Sciences (21 articles)
Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0 in International Journal of Molecular Sciences (7 articles)

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Research

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15 pages, 3328 KiB

Open AccessArticle

Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration

by Alessandra Barbanente, Valentina Gandin, Cecilia Ceresa, Cristina Marzano, Nicoletta Ditaranto, James D. Hoeschele, Giovanni Natile, Fabio Arnesano, Concetta Pacifico, Francesco P. Intini and Nicola Margiotta

Int. J. Mol. Sci. 2022, 23(13), 7081; https://doi.org/10.3390/ijms23137081 - 25 Jun 2022

Cited by 9 | Viewed by 2304

Abstract

Kiteplatin, [PtCl₂(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis,trans,cis-[PtCl₂(OBz)₂(cis-1,4-DACH)] (1; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·10⁶ LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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19 pages, 4252 KiB

Open AccessArticle

New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors

by Watson P. Folk, Alpana Kumari, Tetsushi Iwasaki, Erica K. Cassimere, Slovénie Pyndiah, Elizabeth Martin, Kelly Homlar and Daitoku Sakamuro

Int. J. Mol. Sci. 2021, 22(24), 13324; https://doi.org/10.3390/ijms222413324 - 11 Dec 2021

Cited by 4 | Viewed by 3015

Abstract

The pro-apoptotic tumor suppressor BIN1 inhibits the activities of the neoplastic transcription factor MYC, poly (ADP-ribose) polymerase-1 (PARP1), and ATM Ser/Thr kinase (ATM) by separate mechanisms. Although BIN1 deficits increase cancer-cell resistance to DNA-damaging chemotherapeutics, such as cisplatin, it is not fully understood when BIN1 deficiency occurs and how it provokes cisplatin resistance. Here, we report that the coordinated actions of MYC, PARP1, and ATM assist cancer cells in acquiring cisplatin resistance by BIN1 deficits. Forced BIN1 depletion compromised cisplatin sensitivity irrespective of Ser15-phosphorylated, pro-apoptotic TP53 tumor suppressor. The BIN1 deficit facilitated ATM to phosphorylate the DNA-damage-response (DDR) effectors, including MDC1. Consequently, another DDR protein, RNF8, bound to ATM-phosphorylated MDC1 and protected MDC1 from caspase-3-dependent proteolytic cleavage to hinder cisplatin sensitivity. Of note, long-term and repeated exposure to cisplatin naturally recapitulated the BIN1 loss and accompanying RNF8-dependent cisplatin resistance. Simultaneously, endogenous MYC was remarkably activated by PARP1, thereby repressing the BIN1 promoter, whereas PARP inhibition abolished the hyperactivated MYC-dependent BIN1 suppression and restored cisplatin sensitivity. Since the BIN1 gene rarely mutates in human cancers, our results suggest that simultaneous inhibition of PARP1 and ATM provokes a new BRCAness-independent synthetic lethal effect and ultimately re-establishes cisplatin sensitivity even in platinum-refractory cancer cells. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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24 pages, 7124 KiB

Open AccessArticle

Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin

by Estefanía Moreno-Gordaliza, Maria Dolores Marazuela, Óscar Pastor, Alberto Lázaro and María Milagros Gómez-Gómez

Int. J. Mol. Sci. 2021, 22(22), 12521; https://doi.org/10.3390/ijms222212521 - 20 Nov 2021

Cited by 8 | Viewed by 2824

Abstract

Nephrotoxicity is a major complication of cisplatin-based chemotherapy, leading to acute kidney injury in ca. 30% of patients, with no preventive intervention or treatment available for clinical use. Cilastatin has proved to exert a nephroprotective effect for cisplatin therapies in in vitro and in vivo models, having recently entered clinical trials. A deeper understanding at the molecular level of cisplatin-induced renal damage and the effect of potential protective agents could be key to develop successful nephroprotective therapies and to establish new biomarkers of renal damage and nephroprotection. A targeted lipidomics approach, using LC-MS/MS, was employed for the quantification of 108 lipid species (comprising phospholipids, sphingolipids, and free and esterified cholesterol) in kidney cortex and medulla extracts from rats treated with cisplatin and/or cilastatin. Up to 56 and 63 lipid species were found to be altered in the cortex and medulla, respectively, after cisplatin treatment. Co-treatment with cilastatin attenuated many of these lipid changes, either totally or partially with respect to control levels. Multivariate analysis revealed that lipid species can be used to discriminate renal damage and nephroprotection, with cholesterol esters being the most discriminating species, along with sulfatides and phospholipids. Potential diagnostic biomarkers of cisplatin-induced renal damage and cilastatin nephroprotection were also found. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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14 pages, 4373 KiB

Open AccessArticle

Antagonistic Interaction between Histone Deacetylase Inhibitor: Cambinol and Cisplatin—An Isobolographic Analysis in Breast Cancer In Vitro Models

by Marta Hałasa, Jarogniew J. Łuszczki, Magdalena Dmoszyńska-Graniczka, Marzena Baran, Estera Okoń, Andrzej Stepulak and Anna Wawruszak

Int. J. Mol. Sci. 2021, 22(16), 8573; https://doi.org/10.3390/ijms22168573 - 9 Aug 2021

Cited by 8 | Viewed by 2362

Abstract

Breast cancer (BC) is the leading cause of death in women all over the world. Currently, combined chemotherapy with two or more agents is considered a promising anti-cancer tool to achieve better therapeutic response and to reduce therapy-related side effects. In our study, we demonstrated an antagonistic effect of cytostatic agent-cisplatin (CDDP) and histone deacetylase inhibitor: cambinol (CAM) for breast cancer cell lines with different phenotypes: estrogen receptor positive (MCF7, T47D) and triple negative (MDA-MB-231, MDA-MB-468). The type of pharmacological interaction was assessed by an isobolographic analysis. Our results showed that both agents used separately induced cell apoptosis; however, applying them in combination ameliorated antiproliferative effect for all BC cell lines indicating antagonistic interaction. Cell cycle analysis showed that CAM abolished cell cycle arrest in S phase, which was induced by CDDP. Additionally, CAM increased cell proliferation compared to CDDP used alone. Our data indicate that CAM and CDDP used in combination produce antagonistic interaction, which could inhibit anti-cancer treatment efficacy, showing importance of preclinical testing. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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14 pages, 22547 KiB

Open AccessArticle

Genomic Characterization of Cisplatin Response Uncovers Priming of Cisplatin-Induced Genes in a Resistant Cell Line

by Hadar Golan Berman, Pooja Chauhan, Shira Shalev, Hiba Hassanain, Avital Parnas and Sheera Adar

Int. J. Mol. Sci. 2021, 22(11), 5814; https://doi.org/10.3390/ijms22115814 - 28 May 2021

Cited by 11 | Viewed by 4732

Abstract

Cisplatin is a chemotherapy drug that kills cancer cells by damaging their DNA. In human cells, this damage is repaired primarily by nucleotide excision repair. While cisplatin is generally effective, many cancers exhibit initial or acquired resistance to it. Here, we studied cisplatin resistance in a defined cell line system. We conducted a comprehensive genomic characterization of the cisplatin-sensitive A2780 ovarian cancer cell line compared to A2780cis, its resistant derivative. The resistant cells acquired less damage, but had similar repair kinetics. Genome-wide mapping of nucleotide excision repair showed a shift in the resistant cells from global genome towards transcription-coupled repair. By mapping gene expression changes following cisplatin treatment, we identified 56 upregulated genes that have higher basal expression in the resistant cell line, suggesting they are primed for a cisplatin response. More than half of these genes are novel to cisplatin- or damage-response. Six out of seven primed genes tested were upregulated in response to cisplatin in additional cell lines, making them attractive candidates for future investigation. These novel candidates for cisplatin resistance could prove to be important prognostic markers or targets for tailored combined therapy in the future. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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13 pages, 1646 KiB

Open AccessArticle

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

by Anna Wawruszak, Jarogniew Luszczki, Marta Halasa, Estera Okon, Sebastian Landor, Cecilia Sahlgren, Adolfo Rivero-Muller and Andrzej Stepulak

Int. J. Mol. Sci. 2021, 22(10), 5184; https://doi.org/10.3390/ijms22105184 - 13 May 2021

Cited by 6 | Viewed by 2669

Abstract

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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Review

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23 pages, 941 KiB

Open AccessReview

Can Cisplatin Therapy Be Improved? Pathways That Can Be Targeted

by Reem Ali, Mustapha Aouida, Abdallah Alhaj Sulaiman, Srinivasan Madhusudan and Dindial Ramotar

Int. J. Mol. Sci. 2022, 23(13), 7241; https://doi.org/10.3390/ijms23137241 - 29 Jun 2022

Cited by 36 | Viewed by 5302

Abstract

Cisplatin (cis-diamminedichloroplatinum (II)) is the oldest known chemotherapeutic agent. Since the identification of its anti-tumour activity, it earned a remarkable place as a treatment of choice for several cancer types. It remains effective against testicular, bladder, lung, head and neck, ovarian, and other cancers. Cisplatin treatment triggers different cellular responses. However, it exerts its cytotoxic effects by generating inter-strand and intra-strand crosslinks in DNA. Tumour cells often develop tolerance mechanisms by effectively repairing cisplatin-induced DNA lesions or tolerate the damage by adopting translesion DNA synthesis. Cisplatin-associated nephrotoxicity is also a huge challenge for effective therapy. Several preclinical and clinical studies attempted to understand the major limitations associated with cisplatin therapy, and so far, there is no definitive solution. As such, a more comprehensive molecular and genetic profiling of patients is needed to identify those individuals that can benefit from platinum therapy. Additionally, the treatment regimen can be improved by combining cisplatin with certain molecular targeted therapies to achieve a balance between tumour toxicity and tolerance mechanisms. In this review, we discuss the importance of various biological processes that contribute to the resistance of cisplatin and its derivatives. We aim to highlight the processes that can be modulated to suppress cisplatin resistance and provide an insight into the role of uptake transporters in enhancing drug efficacy. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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33 pages, 1288 KiB

Open AccessReview

The Rationale for “Laser-Induced Thermal Therapy (LITT) and Intratumoral Cisplatin” Approach for Cancer Treatment

by Renan Vieira de Brito, Marília Wellichan Mancini, Marcel das Neves Palumbo, Luis Henrique Oliveira de Moraes, Gerson Jhonatan Rodrigues, Onivaldo Cervantes, Joel Avram Sercarz and Marcos Bandiera Paiva

Int. J. Mol. Sci. 2022, 23(11), 5934; https://doi.org/10.3390/ijms23115934 - 25 May 2022

Cited by 7 | Viewed by 3545

Abstract

Cisplatin is one of the most widely used anticancer drugs in the treatment of various types of solid human cancers, as well as germ cell tumors, sarcomas, and lymphomas. Strong evidence from research has demonstrated higher efficacy of a combination of cisplatin and derivatives, together with hyperthermia and light, in overcoming drug resistance and improving tumoricidal efficacy. It is well known that the antioncogenic potential of CDDP is markedly enhanced by hyperthermia compared to drug treatment alone. However, more recently, accelerators of high energy particles, such as synchrotrons, have been used to produce powerful and monochromatizable radiation to induce an Auger electron cascade in cis-platinum molecules. This is the concept that makes photoactivation of cis-platinum theoretically possible. Both heat and light increase cisplatin anticancer activity via multiple mechanisms, generating DNA lesions by interacting with purine bases in DNA followed by activation of several signal transduction pathways which finally lead to apoptosis. For the past twenty-seven years, our group has developed infrared photo-thermal activation of cisplatin for cancer treatment from bench to bedside. The future development of photoactivatable prodrugs of platinum-based agents injected intratumorally will increase selectivity, lower toxicity and increase efficacy of this important class of antitumor drugs, particularly when treating tumors accessible to laser-based fiber-optic devices, as in head and neck cancer. In this article, the mechanistic rationale of combined intratumor injections of cisplatin and laser-induced thermal therapy (CDDP–LITT) and the clinical application of such minimally invasive treatment for cancer are reviewed. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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27 pages, 2312 KiB

Open AccessReview

Pt(IV) Prodrugs with NSAIDs as Axial Ligands

by Daniil Spector, Olga Krasnovskaya, Kirill Pavlov, Alexander Erofeev, Peter Gorelkin, Elena Beloglazkina and Alexander Majouga

Int. J. Mol. Sci. 2021, 22(8), 3817; https://doi.org/10.3390/ijms22083817 - 7 Apr 2021

Cited by 40 | Viewed by 3757

Abstract

A chemo-anti-inflammatory strategy is of interest for the treatment of aggressive cancers. The platinum (IV) prodrug with non-steroidal anti-inflammatory drugs (NSAIDs) as axial ligands is designed to efficiently enter tumor cells due to high lipophilicity and release the cytotoxic metabolite and NSAID intracellularly, thereby reducing side effects and increasing the therapeutic efficacy of platinum chemotherapy. Over the last 7 years, a number of publications have been devoted to the design of such Pt(IV) prodrugs in combination with anti-inflammatory chemotherapy, with high therapeutic efficacy in vitro and In vivo. In this review, we summarize the studies devoted to the development of Pt(IV) prodrugs with NSAIDs as axial ligands, the study of the mechanism of their cytotoxic action and anti-inflammatory activity, the structure–activity ratio, and therapeutic efficacy. Full article

(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0)

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