Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy

Abstract

Cisplatin and other platinum-based chemotherapeutic drugs have been used extensively for the treatment of human cancers such as bladder, blood, breast, cervical, esophageal, head and neck, lung, ovarian, testicular cancers, and sarcoma. Cisplatin is commonly administered intravenously as a first-line chemotherapy for patients suffering from various malignancies. Upon absorption into the cancer cell, cisplatin interacts with cellular macromolecules and exerts its cytotoxic effects through a series of biochemical mechanisms by binding to Deoxyribonucleic acid (DNA) and forming intra-strand DNA adducts leading to the inhibition of DNA synthesis and cell growth. Its primary molecular mechanism of action has been associated with the induction of both intrinsic and extrinsic pathways of apoptosis resulting from the production of reactive oxygen species through lipid peroxidation, activation of various signal transduction pathways, induction of p53 signaling and cell cycle arrest, upregulation of pro-apoptotic genes/proteins, and down-regulation of proto-oncogenes and anti-apoptotic genes/proteins. Despite great clinical outcomes, many studies have reported substantial side effects associated with cisplatin monotherapy, while others have shown substantial drug resistance in some cancer patients. Hence, new formulations and several combinational therapies with other drugs have been tested for the purpose of improving the clinical utility of cisplatin. Therefore, this review provides a comprehensive understanding of its molecular mechanisms of action in cancer therapy and discusses the therapeutic approaches to overcome cisplatin resistance and side effects.

Targeted Treatment of Head and Neck (Pre)Cancer: Preclinical Target Identification and Development of Novel Therapeutic Applications

“…Cisplatin is the mostly applied cytotoxic drug in chemotherapy regimen, which is often applied in combination with radiotherapy. The drug is able to form both intra-strand and inter-strand crosslinking bridges between the two complementary DNA strands of both the genomic and mitochondrial DNA [ 44 , 45 ]. This covalent inter-strand crosslink hampers DNA replication as the replication fork is challenged to pass the DNA crosslink.…”

Classification and Treatment of Diseases in the Age of Genome Medicine Based on Pathway Pathology

“…Cell death and in particular apoptosis are the major cellular pathways activated by anti-cancer drugs. However, there are relatively few studies that systematically report on the molecular pathways activated by these drugs [98,99]. Cell death is a major cellular pathway in many human diseases and has been molecularly dissected in various subtypes, including apoptosis, necroptosis, immunogenic cell death, etc.…”

Synthesis and Antitumor Activity of (3-Hydroxyacrylato-O,O′) Diammineplatinum(II)

“…Cisplatin, a platinum(II) complex, has made a major impact in the chemotherapeutic treatment of testicular and ovarian cancers since the accidental discovery of its biological activity, and is widely used in the treatment of these types of cancers. 1,2 However, it still has nonnegligible toxic and side effects such as nephrotoxicity, emetogenicity, and drug resistance, which cripple its overall effectiveness in cancer therapy. [3][4][5][6] For decades, thousands of platinum(II) complexes have been prepared in the hope of finding those with more tolerable toxicological profile and higher efficacy.…”