Cisplatin (<i>cis-</i>diamminedichloridoplatinum(II)) has been widely used against testicular, ovarian, cervical, bladder, head and neck cancers, melanoma and lymphomas for several decades. The predominant mechanism of anticancer activity of cisplatin is DNA cross-linking, which interferes with replication and transcription. Despite severe side effects and intrinsic and acquired tumor resistance, cisplatin remains a mainstay of anticancer chemotherapy along with the other platinum derivatives, such as carboplatin and oxaliplatin. Cancer cells acquire resistance to cisplatin by various mechanisms. Copper transport proteins Ctr1, Atox1, ATP7A and ATP7B have all been implicated in modulating cell sensitivity to platinum drugs. Cisplatin binds to the CxxC motifs in copper chaperone Atox1, and in the metal-binding domains of the ATP-driven copper transporters ATP7A and ATP7B, which normally bind copper. Elevated expression of ATP7A and ATP7B has been correlated with cancer resistance to cisplatin, while the role of Atox1 appears to be more complex. In the cell, Atox1 may transfer platinum to the metal binding domains of ATP7B, similar to its function in delivering copper to these proteins. At the same time, Atox1 has been reported to be a transcriptional regulator, suggesting an intriguing possibility that interaction of Atox1-Pt with DNA may potentiate pharmacological activity of cisplatin. Investigation of cisplatin reactions with Atox1 under the physiological redox conditions, and gene-specific DNA cross-link profiling in cancer cells led us to a model that places Atox1 is at the junction of cisplatin detoxification and target delivery pathways.<br/>

Interplay of copper transport proteins in the processing of platinum anticancer drugs in the cell

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.