fig1

Figure 1. Mechanisms of cisplatin toxicity and resistance. Cisplatin is transported either actively by copper transporters such as CTR1 across the plasma membrane or passively through diffusion. Cisplatin can be actively transported out of the cell by metal transporters such as ATP7A and ATP7B and thus overexpression of these transporters is a mechanism of resistance. Cisplatin is hydrolyzed to its active form in the cytosol where it can bind proteins inducing oxidative stress or can be detoxified via cellular antioxidants like GSH. Active cisplatin binds purines on DNA which results in activation of p53 and the DNA damage response. P53 target genes like Bax and cellular stress from oxidative damage activate MOMP formation in the mitochondria, resulting in release of cytochrome c and activation of the apoptosome. Caspase3/7 cleave ICAD which release CAD and cleaves DNA leading to apoptosis. Black arrows notate events that promote toxicity, red arrows notate events that promote resistance. CTR1: copper transporter 1; Cis: cisplatin; GSH: glutathione; Bax: Bcl2 associated X-protein; tBid: truncated - BH3 domain interacting-domain death agonist; ATR: ataxia telengeicstasia and Rad3 related protein; CHK1: checkpoint kinase 1; Cyto C: cytochrome C; MTP: mitochondrial permeability transition pore; IAPs: inhibitors of apoptosis proteins; NRF2: nuclear factor erythroid-derived 2-like