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The Discovery and Development of Cisplatin

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 51002

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Dr. Erica Gentilin

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Bioacoustics Research Laboratory, Department of Neurosciences, Università degli Studi di Padova, 35122 Padua, Italy
Interests: ototoxicity; hearing loss; cisplatin; nanoparticles; regenerative medicine in otorhinolaryngology; decellularization
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Special Issue Information

Dear Colleagues,

Cisplatin (cis-diamminedichloroplatinum (II)) is one of the most broadly used chemotherapies worldwide. It was synthesized for the first time in 1844 by the Italian chemist Michele Peyrone (1813–1883), but it was only in 1965 that it was accidentally identified as an anticancer agent by the biophysical chemist Barnett Rosenberg (1926–2009). In 1978, it was approved by the US Food and Drug Administration (FDA) as an anticancer treatment for patients with testicular and bladder cancer. Since then, cisplatin has been used to treat many neoplasms affecting several millions of patients as part of an approved therapeutic regimen or clinical study.

This Special Issue seeks to provide a roundtable where researchers with different backgrounds can contribute with their findings to this highly relevant field. Therefore, the scope of the issue encompasses, but is not restricted to, the following areas: the unexpected events leading the discovery of cisplatin’s antitumor action, its introduction to clinical practice, the comprehension of its mechanism of action and the ongoing research to overcome cisplatin resistance. The use of cisplatin is associated with numerous side effects, including nephrotoxicity, neurotoxicity and ototoxicity. Nephrotoxicity may be reduced or prevented by intravenous hydration, while neurotoxicity and ototoxicity are still lacking therapeutic and preventive treatments. Despite the success of cisplatin in cancer therapy, extensive research efforts have been devoted to improving the cisplatin formula, aiming to limit adverse events. Therefore, contributions to this issue, in the form of both original research and review articles, could cover any aspect of the development of new platinum-based strategies maintaining anticancer activity and simultaneously avoiding the known side effects.

Dr. Erica Gentilin
Guest Editor

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Keywords

cisplatin
cisplatin synthesis
mechanism of action
anticancer drugs
drug resistance
side effects

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

2 pages, 181 KiB

Open AccessEditorial

New Advancements in Cisplatin-Based Treatments

by Erica Gentilin

Int. J. Mol. Sci. 2023, 24(6), 5920; https://doi.org/10.3390/ijms24065920 - 21 Mar 2023

Cited by 4 | Viewed by 1863

Abstract

Cisplatin (cis-diamminedichloroplatinum (II)) is one of the most broadly used chemotherapies worldwide [...] Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

Research

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17 pages, 5886 KiB

Open AccessArticle

Liquid Crystalline Nanoparticles Conjugated with Dexamethasone Prevent Cisplatin Ototoxicity In Vitro

by Filippo Valente, Edi Simoni, Erica Gentilin, Alessandro Martini, Elisabetta Zanoletti, Gino Marioni, Piero Nicolai and Laura Astolfi

Int. J. Mol. Sci. 2022, 23(23), 14881; https://doi.org/10.3390/ijms232314881 - 28 Nov 2022

Cited by 4 | Viewed by 2140

Abstract

The conjugation of drugs with nanoparticles represents an innovative approach for controlled and targeted administration of therapeutic agents. Nanoparticle-based systems have been tested for the inner ear therapy, increasing the drug diffusion and being detected in all parts of the cochlea when locally applied near the round window. In this study, glycerol monooleate liquid crystalline NanoParticles were conjugated with Dexamethasone (NPD), a hydrophobic drug already used for inner ear treatments but defective in solubility and bioavailability. NPD has been tested in vitro in the cell line OC-k3, a model of sensory cells of the inner ear, and the therapeutic efficacy has been evaluated against cisplatin, a chemotherapeutic compound known to induce ototoxicity. After comparing the physical chemical characteristics of NPD to the equivalent naïve nanoparticles, an initial investigation was carried out into the nanoparticle’s uptake in OC-k3 cells, which takes place within a few hours of treatment without causing toxic damage up to a concentration of 50 µg/mL. The NPD delivered the dexamethasone inside the cells at a significantly increased rate compared to the equivalent free drug administration, increasing the half-life of the therapeutic compound within the cell. Concerning the co-treatment with cisplatin, the NPD significantly lowered the cisplatin cytotoxicity after 48 h of administration, preventing cell apoptosis. To confirm this result, also cell morphology, cell cycle and glucocorticoids receptor expression were investigated. In conclusion, the NPD system has thus preliminarily shown the potential to improve the therapeutic efficacy of treatments delivered in the inner ear and prevent drug-induced ototoxicity. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

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15 pages, 2513 KiB

Open AccessArticle

Diclofenac Sensitizes Signet Ring Cell Gastric Carcinoma Cells to Cisplatin by Activating Autophagy and Inhibition of Survival Signal Pathways

by Nang Lae Lae Phoo, Amonnat Sukhamwang, Pornngarm Dejkriengkraikul and Supachai Yodkeeree

Int. J. Mol. Sci. 2022, 23(20), 12066; https://doi.org/10.3390/ijms232012066 - 11 Oct 2022

Cited by 8 | Viewed by 2225

Abstract

Gastric cancer has one of the highest incidence rates of cancer worldwide while also contributing to increased drug resistance among patients in clinical practice. Herein, we have investigated the role of diclofenac (DCF) on sensitizing cisplatin resistance in signet ring cell gastric carcinoma cells (SRCGC). Non-toxic concentrations of DCF significantly augmented cisplatin-induced cell death in cisplatin-resistant SRCGC cells (KATO/DDP) but not in cisplatin-sensitive SRCGC cells (KATOIII). Consistently, concomitant treatment of DCF and cisplatin significantly enhanced autophagic cell death due to overproduction of intracellular reactive oxygen species (ROS). At the molecular level, the induction of ROS has been associated with a reduction in antioxidant enzymes expression while inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Moreover, the combination of DCF and cisplatin also inhibited the expression of survival proteins including Bcl-2, Bcl-xL, cIAP1 and cyclin D1 in KATO/DDP cells when compared with cisplatin alone. This was due, at least in part, to reduce MAPKs, Akt, NF-κB, AP-1 and STAT-3 activation. Taken together, our results suggested that DCF potentiated the anticancer effect of cisplatin in SRCGC via the regeneration of intracellular ROS, which in turn promoted cell death as an autophagy mechanism and potentially modulated the cell survival signal transduction pathway. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

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17 pages, 3332 KiB

Open AccessArticle

Nimodipine Treatment Protects Auditory Hair Cells from Cisplatin-Induced Cell Death Accompanied by Upregulation of LMO4

by Saskia Fritzsche, Christian Strauss, Christian Scheller and Sandra Leisz

Int. J. Mol. Sci. 2022, 23(10), 5780; https://doi.org/10.3390/ijms23105780 - 21 May 2022

Cited by 7 | Viewed by 2618

Abstract

Ototoxicity is one of the main dose-limiting side effects of cisplatin chemotherapy and impairs the quality of life of tumor patients dramatically. Since there is currently no established standard therapy targeting hearing loss in cisplatin treatment, the aim of this study was to investigate the effect of nimodipine and its role in cell survival in cisplatin-associated hearing cell damage. To determine the cytotoxic effect, the cell death rate was measured using undifferentiated and differentiated UB/OC−1 and UB/OC−2 cells, after nimodipine pre-treatment and stress induction by cisplatin. Furthermore, immunoblot analysis and intracellular calcium measurement were performed to investigate anti-apoptotic signaling, which was associated with a reduced cytotoxic effect after nimodipine pre-treatment. Cisplatin’s cytotoxic effect was significantly attenuated by nimodipine up to 61%. In addition, nimodipine pre-treatment counteracted the reduction in LIM Domain Only 4 (LMO4) by cisplatin, which was associated with increased activation of Ak strain transforming/protein kinase B (Akt), cAMP response element-binding protein (CREB), and signal transducers and activators of transcription 3 (Stat3). Thus, nimodipine presents a potentially well-tolerated substance against the ototoxicity of cisplatin, which could result in a significant improvement in patients’ quality of life. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

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12 pages, 2210 KiB

Open AccessArticle

Beyond Single-Cell Analysis of Metallodrugs by ICP-MS: Targeting Cellular Substructures

by Audrey Galé, Lukas Hofmann, Nicola Lüdi, Martin Nils Hungerbühler, Christoph Kempf, Johannes Thomas Heverhagen, Hendrik von Tengg-Kobligk, Peter Broekmann and Nico Ruprecht

Int. J. Mol. Sci. 2021, 22(17), 9468; https://doi.org/10.3390/ijms22179468 - 31 Aug 2021

Cited by 11 | Viewed by 4009

Abstract

Platinum compounds such as cisplatin (cisPt) embody the backbone of combination chemotherapy protocols against advanced lung cancer. However, their efficacy is primarily limited by inherent or acquired platinum resistance, the origin of which has not been fully elucidated yet, although of paramount interest. Using single cell inductively coupled plasma mass spectrometry (SC-ICP-MS), this study quantifies cisPt in single cancer cells and for the first time in isolated nuclei. A comparison of cisPt uptake was performed between a wild type (wt) cancer cell line and related resistant sublines. In both, resistant cells, wt cells, and their nuclei, cisPt uptake was measured at different incubation times. A lower amount of cisPt was found in resistant cell lines and their nuclei compared to wt cells. Moreover, the abundance of internalized cisPt decreased with increasing resistance. Interestingly, concentrations of cisPt found within the nuclei were higher than compared to cellular concentrations. Here, we show, that SC-ICP-MS allows precise and accurate quantification of metallodrugs in both single cells and cell organelles such as nuclei. These findings pave the way for future applications investigating the potency and efficacy of novel metallodrugs developed for cancer treatment. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

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11 pages, 1542 KiB

Open AccessArticle

Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice

by Patrizia Garbati, Raffaella Barbieri, Matilde Calderoni, Francesca Baldini, Mario Nizzari, Paola Modesto, Tullio Florio and Aldo Pagano

Int. J. Mol. Sci. 2021, 22(13), 6753; https://doi.org/10.3390/ijms22136753 - 23 Jun 2021

Cited by 5 | Viewed by 2558

Abstract

High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

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Review

Jump to: Editorial, Research

30 pages, 1695 KiB

Open AccessReview

Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity

by Ivan K. Domingo, Asna Latif and Amit P. Bhavsar

Int. J. Mol. Sci. 2022, 23(13), 7227; https://doi.org/10.3390/ijms23137227 - 29 Jun 2022

Cited by 33 | Viewed by 5059

Abstract

Cisplatin is a platinum-based chemotherapeutic that has long since been effective against a variety of solid-cancers, substantially improving the five-year survival rates for cancer patients. Its use has also historically been limited by its adverse drug reactions, or cisplatin-induced toxicities (CITs). Of these reactions, cisplatin-induced nephrotoxicity (CIN), cisplatin-induced peripheral neuropathy (CIPN), and cisplatin-induced ototoxicity (CIO) are the three most common of several CITs recognised thus far. While the anti-cancer activity of cisplatin is well understood, the mechanisms driving its toxicities have only begun to be defined. Most of the literature pertains to damage caused by oxidative stress that occurs downstream of cisplatin treatment, but recent evidence suggests that the instigator of CIT development is inflammation. Cisplatin has been shown to induce pro-inflammatory signalling in CIN, CIPN, and CIO, all of which are associated with persisting markers of inflammation, particularly from the innate immune system. This review covered the hallmarks of inflammation common and distinct between different CITs, the role of innate immune components in development of CITs, as well as current treatments targeting pro-inflammatory signalling pathways to conserve the use of cisplatin in chemotherapy and improve long-term health outcomes of cancer patients. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

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25 pages, 1303 KiB

Open AccessReview

Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy

by Shaloam Dasari, Sylvianne Njiki, Ariane Mbemi, Clement G. Yedjou and Paul B. Tchounwou

Int. J. Mol. Sci. 2022, 23(3), 1532; https://doi.org/10.3390/ijms23031532 - 28 Jan 2022

Cited by 120 | Viewed by 14746

Abstract

Cisplatin and other platinum-based drugs, such as carboplatin, ormaplatin, and oxaliplatin, have been widely used to treat a multitude of human cancers. However, a considerable proportion of patients often relapse due to drug resistance and/or toxicity to multiple organs including the liver, kidneys, gastrointestinal tract, and the cardiovascular, hematologic, and nervous systems. In this study, we sought to provide a comprehensive review of the current state of the science highlighting the use of cisplatin in cancer therapy, with a special emphasis on its molecular mechanisms of action, and treatment modalities including the combination therapy with natural products. Hence, we searched the literature using various scientific databases., such as MEDLINE, PubMed, Google Scholar, and relevant sources, to collect and review relevant publications on cisplatin, natural products, combination therapy, uses in cancer treatment, modes of action, and therapeutic strategies. Our search results revealed that new strategic approaches for cancer treatment, including the combination therapy of cisplatin and natural products, have been evaluated with some degree of success. Scientific evidence from both in vitro and in vivo studies demonstrates that many medicinal plants contain bioactive compounds that are promising candidates for the treatment of human diseases, and therefore represent an excellent source for drug discovery. In preclinical studies, it has been demonstrated that natural products not only enhance the therapeutic activity of cisplatin but also attenuate its chemotherapy-induced toxicity. Many experimental studies have also reported that natural products exert their therapeutic action by triggering apoptosis through modulation of mitogen-activated protein kinase (MAPK) and p53 signal transduction pathways and enhancement of cisplatin chemosensitivity. Furthermore, natural products protect against cisplatin-induced organ toxicity by modulating several gene transcription factors and inducing cell death through apoptosis and/or necrosis. In addition, formulations of cisplatin with polymeric, lipid, inorganic, and carbon-based nano-drug delivery systems have been found to delay drug release, prolong half-life, and reduce systemic toxicity while other formulations, such as nanocapsules, nanogels, and hydrogels, have been reported to enhance cell penetration, target cancer cells, and inhibit tumor progression. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

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17 pages, 377 KiB

Open AccessReview

Integrated Medicine for Chemotherapy-Induced Peripheral Neuropathy

by Chih-Hung Tsai, Yuan-Ho Lin, Yung-Sheng Li, Trung-Loc Ho, Le Huynh Hoai Thuong and Yu-Huei Liu

Int. J. Mol. Sci. 2021, 22(17), 9257; https://doi.org/10.3390/ijms22179257 - 26 Aug 2021

Cited by 9 | Viewed by 4065

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of typical chemotherapeutics among cancer survivors. Despite the recent progress, the effective prevention and treatment strategies for CIPN remain limited. Better understanding of the pathogenesis of CIPN may provide new niches for developing a new ideal therapeutic strategy. This review summarizes the current understanding of CIPN and current recommendations along with completed/active clinical trials and aims to foster translational research to improve the development of effective strategies for managing CIPN. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

18 pages, 1054 KiB

Open AccessReview

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

by Robert Csaba Kiss, Fen Xia and Scarlett Acklin

Int. J. Mol. Sci. 2021, 22(15), 8199; https://doi.org/10.3390/ijms22158199 - 30 Jul 2021

Cited by 65 | Viewed by 8601

Abstract

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance. Full article

(This article belongs to the Special Issue The Discovery and Development of Cisplatin)

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