Tchounwou Paul B, Dasari Shaloam, Noubissi Felicite K, Ray Paresh, Kumar Sanjay
Cellomics and Toxicogenomics Research Laboratory, NIH-RCMI Center for Health Disparities Research, Jackson State University, Jackson, MS, USA.
Department of Chemistry and Biochemistry, College of Science, Engineering and Technology, Jackson State University, Jackson, MS, USA.
J Exp Pharmacol. 2021 Mar 18;13:303-328. doi: 10.2147/JEP.S267383. eCollection 2021.
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.
顺铂和其他铂类化疗药物已被广泛用于治疗人类癌症，如膀胱癌、血癌、乳腺癌、宫颈癌、食管癌、头颈癌、肺癌、卵巢癌、睾丸癌和肉瘤。顺铂通常作为一线化疗药物通过静脉注射给药，用于治疗各种恶性肿瘤患者。进入癌细胞后，顺铂与细胞大分子相互作用，并通过一系列生化机制发挥其细胞毒性作用，即与脱氧核糖核酸（DNA）结合，形成链内DNA加合物，从而抑制DNA合成和细胞生长。其主要分子作用机制与诱导凋亡的内在和外在途径有关，这是由脂质过氧化产生的活性氧、各种信号转导途径的激活、p53信号传导和细胞周期停滞的诱导、促凋亡基因/蛋白质的上调以及原癌基因和抗凋亡基因/蛋白质的下调所导致的。尽管临床疗效显著，但许多研究报告了顺铂单药治疗的大量副作用，而其他研究则表明一些癌症患者存在显著的耐药性。因此，为了提高顺铂的临床效用，已经测试了新的制剂和几种与其他药物的联合疗法。因此，本综述全面阐述了其在癌症治疗中的分子作用机制，并讨论了克服顺铂耐药性和副作用的治疗方法。
