Elsevier

European Journal of Pharmacology

Volume 740, 5 October 2014, Pages 364-378
European Journal of Pharmacology

Review
Cisplatin in cancer therapy: Molecular mechanisms of action

https://doi.org/10.1016/j.ejphar.2014.07.025Get rights and content

Abstract

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used. Furthermore, combination therapies of cisplatin with other drugs have been highly considered to overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in combination with other drugs) for the treatment of various human cancers. A special attention is paid to its molecular mechanisms of action, and its undesirable side effects.

Introduction

Cisplatin (CAS no. 15663-27-1, MF-Cl2H6N2Pt; NCF-119875), cisplatinum, also called cis-diamminedichloroplatinum(II), is a metallic (platinum) coordination compound with a square planar geometry (The chemical book database, 2014). It is a white or deep yellow to yellow–orange crystalline powder at room temperature. It is slightly soluble in water and soluble in dimethylprimanide and N,N-dimethylformamide. Cisplatin is stable under normal temperatures and pressures, but may transform slowly over time to the trans-isomer (IARC, 1981, Akron, 2009). Cisplatin has a molecular weight of 301.1 g/mol, a density of 3.74 g/cm3, a melting point of 270 °C, a log Kow of −2.19 and a water solubility of 2.53 g/L at 25 °C (HSDB, 2014).

Cisplatin was first synthesized by M. Peyrone in 1844 and its chemical structure was first elucidated by Alfred Werner in 1893. However, the compound did not gain scientific investigations until the 1960s when the initial observations of Rosenberg et al. (1965) at Michigan State University pointed out that certain electrolysis products of platinum mesh electrodes were capable of inhibiting cell division in Escherichia coli created much interest in the possible use of these products in cancer chemotherapy. Since the identification of cis-dichlorodiammineplatinum (II) (cisplatin, r) as the agent responsible for this activity, considerable interest has been generated in the use of coordination complexes of platinum, palladium, and other noble metals in the treatment of cancer.

Cisplatin has been especially interesting since it has shown anticancer activity in a variety of tumors including cancers of the ovaries, testes, and solid tumors of the head and neck. It was discovered to have cytotoxic properties in the 1960s, and by the end of the 1970s it had earned a place as the key ingredient in the systemic treatment of germ cell cancers. Among many chemotherapy drugs that are widely used for cancer, cisplatin is one of the most compelling ones. It was the first FDA-approved platinum compound for cancer treatment in 1978 (Kelland, 2007). This has led to interest in platinum (II)—and other metal—containing compounds as potential anticancer drugs (Frezza et al., 2010).

Cisplatin is clinically proven to combat different types of cancers including sarcomas, cancers of soft tissue, bones, muscles, and blood vessels. Although such cancers have recently received better prognosis and therefore have become less life threatening (Desoize and Madoulet, 2002), significant challenges remain with regard to their cure. Also, because of drug resistance and considerable side effects, combination therapy of cisplatin with other cancer drugs has been applied as novel therapeutic strategies for many human cancers. In this research, we aim to provide a comprehensive review of the physicochemical properties of cisplatin and related platinum-based drugs, to discuss its uses (either alone or in combination with other drugs) for the treatment of various human cancers, to examine its molecular mechanisms of action, and to discuss it potential side effects.

Section snippets

Cisplatin and other platinum-containing drugs

Since the early seminal work in the preclinical and clinical development of cisplatin, several thousand analogs have been synthesized and tested for properties that would enhance its therapeutic index. About 13 of these analogs have been evaluated in clinical trials, but only one (carboplatin) has provided definite advantage over cisplatin and achieved worldwide approval. Nine platinum analogs are currently in clinical trials around the world ormaplatin (tetraplatin), oxaliplatin, DWA2114R,

Cisplatin and lung cancer

Lung cancer remains one of the most common types of fatal malignancies (Youlden et al., 2008). Small cell lung cancers (SCLCs) represent 15% of all lung cancers (Chen et al., 2009). At present, platinum based treatments are key drugs for SCLC (Abrams et al., 2003). Cisplatin and carboplatin are two of the most common types of platinum based treatments used in SCLC chemotherapy (Go and Adjei, 1999). In clinical trials, cisplatin is often selected due to its strong antitumor activity, but its

Combination therapy of cisplatin with other cancer drugs

Cisplatin combination chemotherapy is the basis of treatment of many cancers. Platinum responsiveness is high primarily but many cancer patients will ultimately relapse with cisplatin-resistant disease. Hence, drug resistance has been observed in many patients who have relapsed from cisplatin treatment. The proposed mechanisms of cisplatin resistance include changes in cellular uptake and efflux of cisplatin, increased biotransformation and detoxification in the liver, and increase in DNA

Molecular mechanisms of cisplatin pharmacology

Several membrane transporters of platinum compounds analogous to MDR1 including the efflux ATPases (MRPs, ATP7A/B), and the solute carrier importers (CTR1, the SLCs, AQP2, and AQP9), have been reported. MDR1 is an ATP-binding cassette transporter known for years as P-glycoprotein (Shen et al., 2012, Johnson et al., 1996). The uptake of cisplatin is mediated by the copper transporter Ctr1 in yeast and mammals (Ishida et al., 2002). It has been further confirmed in human cells that cisplatin

Toxicological effects of cisplatin

Cisplatin interacts with DNA, and forms covalent adduct with purine DNA bases and this platinum compound, interaction is the root cause for cytotoxic effect of cisplatin (Yousef et al., 2009). Cisplatin treatment has been associated with several toxic side effects including nephrotoxicity (de Jongh et al., 2003), hepatotoxicity and Cardiotoxicity (Al-Majed, 2007). Many cardiac events have been reported in many case reports including electro-cardiographicchanges, arrhythmias, myocarditis,

Conclusions

Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It has been extensively used for the cure of different types of neoplasms including head and neck, lung, ovarian, leukemia, breast, brain, kidney and testicular cancers. In general, cisplatin and other platinum-based compounds are considered as cytotoxic drugs which kill cancer cells by damaging DNA, inhibiting DNA synthesis and mitosis, and inducing apoptotic cell death. Several molecular

Acknowledgments

The research described in this publication was made possible by a grant from the National Institutes of Health (Grant no. G12MD007581) through the RCMI Center for Environmental Health at Jackson State University.

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