Identifying and Targeting Cellular Mechanisms to Enhance Cisplatin Chemotherapeutic Response in Cancer.

摘要

Cisplatin is one of the most effective and widely used anticancer agents used especially in treating testicular, ovarian, head and neck and lung cancers. As in the case of many chemotherapeutic drugs, a clinical limitation is cancer recurrence and resistance. Cisplatin targets DNA and forms distinct lesions which block DNA replication and transcription. These lesions mediate the cisplatin cytotoxic response and their repair is detrimental to drug cytotoxicity. Cancers exhibit altered repair of cisplatin-DNA lesions leading to drug resistance. Thus, targeting the DNA repair mechanisms is important for increasing cisplatin efficacy. This study validates XPF/ERCC1, a DNA repair enzyme complex, as an important molecular target to enhance cisplatin sensitivity in cancer cells globally. XPF/ERCC1 is vital to the repair of all forms of cisplatin-DNA damage and hence important in mediating clinical response to cisplatin. XPF/ERCC1 enhances cisplatin cytotoxicity by inhibiting the repair of DNA damage. Our studies next identify small molecules that inhibit XPF/ERCC1 in primary and secondary in vitro screens. These compounds potentiate cisplatin sensitivity in cancer cells by inhibiting the repair of cisplatin-DNA damage. Further studies with these compounds could yield inhibitors which can clinically potentiate the effects of cisplatin and result in lower doses of cisplatin being administered while enhancing the cytotoxic effect. Our studies also identify gap junctions and their mediated intercellular communication as an important mechanism in maintaining cisplatin sensitivity. We show that gap junctional intercellular communication induces a bystander effect after cisplatin treatment in untreated bystander cells and hence further potentiates cisplatin's effect. The bystander effect elicits as DNA Double Strand Breaks (DSBs) and further sensitizes XPF/ERCC1 knockdown cells to cisplatin. Further studies might help identify the "signal" that induces DSBs in bystander cells and how unrepaired DNA damage enhances the bystander effect. Studies delineating mechanisms that mediate resistance or maintain sensitivity are important in improving platinum-based therapeutics.