The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

Abstract

Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum-DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely.

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

“…However, the underlying mechanisms are still far from elucidated. The main mechanisms of platinum-based drug resistance are possibly associated with changed cellular platinum accumulation, increased detoxification system, increased DNA repair, decreased apoptosis, and autophagy ( Figure 1 ) ( Kehe and Szinicz, 2005 ; Wheate et al, 2010 ; Zhou et al, 2020 ).…”

“…The way that platinum enters the cell is thought to be passive diffusion and through gated channels ( Gately and Howell, 1993 ; Puckett et al, 2010 ). There are multiple transporters involved in platinum influx/efflux ( Zhou et al, 2020 ), such as solute carrier superfamily (SLCs) of membrane transporters ( Perland and Fredriksson, 2017 ), copper transporter 1/2(CTR1/2) ( Holzer and Howell, 2006 ), copper-transporting ATPases (ATP 7A/7B) ( Gupta and Lutsenko, 2009 ), multidrug resistance protein subfamily (MPR) ( Yaneff et al, 2019 ) etc. The organic cation transporters and copper transporter are related to the influx, while ATP 7A/7B and MPR2 are involved in the isolation and efflux of platinum agents ( Zhou et al, 2020 ).…”

“…This binding depletes cytoplasmic antioxidant reserves and results in the oxidative stress in cells. On the other hand, while the cytoplasmic nucleophiles level is elevated, the available reactive cisplatin would be diminished and thus contribute to cisplatin resistance ( Dilruba and Kalayda, 2016 ; Zhou et al, 2020 ). Thirdly, the DNA repair process is significantly increased in platinum resistance cells ( Wynne et al, 2007 ).…”

<p>Genetic Polymorphisms and the Efficacy of Platinum-Based Chemotherapy: Review</p>

“…Chemotherapy resistance is the innate and/or acquired ability of cancer cells to evade chemotherapeutics' effects, and that is one of the causes of individual variation in PBC response. 20 Previous studies on variability responses to platinumbased chemotherapy suggest that it is affected by the mechanism of how platinum is processed in the body, including pharmacokinetics and pharmacodynamics. In general, efforts have delivered evidence regarding DNA repair systems of tumor cells, and drug metabolization systems cause these variabilities in PBC response.…”

“…In general, efforts have delivered evidence regarding DNA repair systems of tumor cells, and drug metabolization systems cause these variabilities in PBC response. 20,21 Chemotherapy resistance can occur through many mechanisms such as; damage in the drug delivery system, increased efflux and/or decreased drug influx, increased detoxification rate, alteration of the target site, increased damaged-DNA repair activity manifested in tolerance of DNA damage, increased anti-apoptotic factors and/or decreased pro-apoptotic factors, as well as changes in cell cycle/transcription factors. 9 Pharmacokinetic mechanisms include a reduction in drug levels at the target site due to reduced uptake and/or increased efflux by Adenosine triphosphate-binding cassette (ABC) transporters, drug detoxication by glutathione S-transferases (GSTs), and drug elimination by Organic Cation Transporter (OCT) along with Multidrug Toxin Extrusion (MATE).…”