Cisplatin Resistance: Genetic and Epigenetic Factors Involved

Abstract

Cisplatin (CDDP) is the drug of choice against different types of cancer. However, tumor cells can acquire resistance to the damage caused by cisplatin, generating genetic and epigenetic changes that lead to the generation of resistance and the activation of intrinsic resistance mechanisms in cancer cells. Among them, we can find mutations, alternative splicing, epigenetic-driven expression changes, and even post-translational modifications of proteins. However, the molecular mechanisms by which CDDP resistance develops are not clear but are believed to be multi-factorial. This article highlights a description of cisplatin, which includes action mechanism, resistance, and epigenetic factors involved in cisplatin resistance.

USP28 promotes tumorigenesis and cisplatin resistance by deubiquitinating MAST1 protein in cancer cells

“…Cisplatin treatment leads to a high level of drug resistance in patients and recurrence of tumors with cisplatin resistance is frequently observed. Several factors contribute to acquired resistance such as increased drug efflux, activation or inactivation of pro-apoptotic cellular signaling and DNA-adduct repair [ 5 , 34 , 35 ]. Thus, identifying the mechanism of acquired resistance to cisplatin treatment is critical.…”

Cisplatin in Liver Cancer Therapy

“…However, in cells with low chloride concentrations (4 mM), the chloride ligand is hydrolyzed and replaced by a water molecule [ 18 , 40 ]. Hydrolyzed cisplatin is highly reactive and serves as a potent electrophile reacting with nucleophiles such as nitrogen atoms of nucleic acids and SH groups of proteins, which are variously covalently bound to DNA, forming covalent DNA adducts [ 19 , 40 , 41 ]. Platinum atoms bind preferentially to the nitrogen atom at position 7 of the guanine and adenine bases in particular, bridging two adjacent purine bases [ 19 , 40 , 41 ].…”

“…Hydrolyzed cisplatin is highly reactive and serves as a potent electrophile reacting with nucleophiles such as nitrogen atoms of nucleic acids and SH groups of proteins, which are variously covalently bound to DNA, forming covalent DNA adducts [ 19 , 40 , 41 ]. Platinum atoms bind preferentially to the nitrogen atom at position 7 of the guanine and adenine bases in particular, bridging two adjacent purine bases [ 19 , 40 , 41 ]. Most of the cross-links formed by these adducts (approximately 90%) are the 1,2-intrastrand cross-links (1,2-intrastrand (GpG) and 1,2-intrastrand (ApG)); a smaller proportion of interstrand cross-links and monofunctional adducts are also formed [ 19 , 40 , 42 , 43 ].…”

Pioglitazone enhances cisplatin’s impact on triple-negative breast cancer: Role of PPARγ in cell apoptosis

“…In addition, avoiding apoptosis is another important mechanism by which cancer cells can exhibit treatment resistance and promote tumor growth. For instance, resistance to cisplatin can be induced by escaping apoptosis ( Tchounwou et al, 2021 ) and may result from the dysfunction of apoptotic proteins and signaling pathways ( Lugones et al, 2022 , Zhu et al, 2016 ). However, other pathways have been proven to mediate apoptosis in cancer cells, activation of which may relieve chemoresistance.…”