Forgie, B.N.; Prakash, R.; Telleria, C.M. Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives. Int. J. Mol. Sci.2022, 23, 15410.
Forgie, B.N.; Prakash, R.; Telleria, C.M. Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives. Int. J. Mol. Sci. 2022, 23, 15410.
Forgie, B.N.; Prakash, R.; Telleria, C.M. Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives. Int. J. Mol. Sci.2022, 23, 15410.
Forgie, B.N.; Prakash, R.; Telleria, C.M. Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives. Int. J. Mol. Sci. 2022, 23, 15410.
Abstract
Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER-stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.
Keywords
cisplatin; carboplatin; oxaliplatin; cellular uptake; DNA damage; transcription regulation; non-nuclear targets; chemoresistance; mechanisms of action; clinical usages; influx and efflux pumps; ribosome biogenesis; ER stress response; immunogenic cell death; interstrand and intrastrand DNA cross-links.
Subject
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
