Figure 1.

Mechanism of cisplatin resistance. Ligand binding to transforming growth factor beta (TGF-β) receptor initiates intracellular signaling through Smad protein complex (SPC). In the nucleus, SPC bind with the DNA binding domain which results in expression of p21/Waf1 and Nrf2 gene. p21/Waf1 and Nrf2 gene products tightly regulate glutathione metabolism. Cisplatin enters cells by passive diffusion. At low chloride ion concentration, the chloride ion of cisplatin is replaced with water molecules and forms activated cisplatin (aquation). Activated cisplatin enters the nucleus and results into the transcription of genes involved in anticancer activity. Glutathione conjugation with cisplatin hinders its nuclear translocation and thereby its chemo-preventive potential resulting into cisplatin resistance