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.
Highlights
Ever since cisplatin, the first generation of platinum antitumor agents, was approved by the U.S Food and Drug Administration for the treatment of testicular cancer, the development of platinum antitumor agents has explosively grown during the last forty years
The results indicated that OCT2 demethylation cracks open oxaliplatin resistance in renal cell carcinoma (RCC) (Aguilar, 2016) and it highlights the huge potentiality of targeting transporters in clinical application
Kristin et al (Bompiani et al, 2016) knocked out the Copper transporter 1 (CTR1), CTR2, ATOX1, and CCS using CRISPR-Cas9 genome editing; and the results indicated that the loss of CTR1, CTR2, ATOX1, or CCS had little impact on cisplatin sensitivity in both human HEK-293T and ovarian carcinoma OVCAR8 cells
Summary
The first generation of platinum antitumor agents, was approved by the U.S Food and Drug Administration for the treatment of testicular cancer, the development of platinum antitumor agents has explosively grown during the last forty years. Deletion of the yeast CTR1 gene reduces the intracellular accumulation of cisplatin and leads to cisplatin-resistance (Ishida et al, 2002), while forced overexpression of hCTR1 sensitizes small cell lung cancer cells to cisplatin, carboplatin, and oxaliplatin (Song et al, 2004).
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