Can Cisplatin Therapy Be Improved? Pathways That Can Be Targeted

Abstract

Cisplatin (cis-diamminedichloroplatinum (II)) is the oldest known chemotherapeutic agent. Since the identification of its anti-tumour activity, it earned a remarkable place as a treatment of choice for several cancer types. It remains effective against testicular, bladder, lung, head and neck, ovarian, and other cancers. Cisplatin treatment triggers different cellular responses. However, it exerts its cytotoxic effects by generating inter-strand and intra-strand crosslinks in DNA. Tumour cells often develop tolerance mechanisms by effectively repairing cisplatin-induced DNA lesions or tolerate the damage by adopting translesion DNA synthesis. Cisplatin-associated nephrotoxicity is also a huge challenge for effective therapy. Several preclinical and clinical studies attempted to understand the major limitations associated with cisplatin therapy, and so far, there is no definitive solution. As such, a more comprehensive molecular and genetic profiling of patients is needed to identify those individuals that can benefit from platinum therapy. Additionally, the treatment regimen can be improved by combining cisplatin with certain molecular targeted therapies to achieve a balance between tumour toxicity and tolerance mechanisms. In this review, we discuss the importance of various biological processes that contribute to the resistance of cisplatin and its derivatives. We aim to highlight the processes that can be modulated to suppress cisplatin resistance and provide an insight into the role of uptake transporters in enhancing drug efficacy.

Keywords: DNA repair; cisplatin; cisplatin resistance; platinum sensitisation.

Figure 1

Chemical structure. Illustrations created by BioRender.com (accessed on 8 May 2022).

Figure 2

Cisplatin DNA adducts are formed when cisplatin exchange one or two of its chloride molecules for water and bind covalently to the purines at the N7 position to form (A) Cisplatin intra-strand adduct or (B) Cisplatin inter-strand crosslink. Illustrations created by BioRender.com (accessed on 8 May 2022).