Journal of Experimental Pharmacology (Mar 2021)
Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy
Abstract
Paul B Tchounwou,1 Shaloam Dasari,1 Felicite K Noubissi,1 Paresh Ray,2 Sanjay Kumar3 1Cellomics and Toxicogenomics Research Laboratory, NIH-RCMI Center for Health Disparities Research, Jackson State University, Jackson, MS, USA; 2Department of Chemistry and Biochemistry, College of Science, Engineering and Technology, Jackson State University, Jackson, MS, USA; 3Department of Life Sciences, School of Earth, Biological, and Environmental Sciences, Central University of South Bihar, Gaya, IndiaCorrespondence: Paul B TchounwouNIH-RCMI Center for Health Disparities Research, Jackson State University, 1400 JR Lynch Street, Jackson, MS, 39217, USATel +1 601-979-0777Fax +1 601-979-0570Email [email protected]: 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.Keywords: cisplatin, molecular mechanisms of action, combination therapy, cancer treatment
