Nitric oxide and cisplatin resistance: NO easy answers

Cisplatin is one of the most widely used chemotherapeutic drugs for treating cancer. Initially, platinum-based therapies are very effective in treating a wide array of cancers; however, recurrence and resistance remain the major limitation to curative therapies (1). Although cisplatin resistance is clearly multifactorial in nature, increased levels of cellular thiols are often associated with the cisplatin-resistant phenotype (2). Cellular thiols, which include glutathione (GSH), can sequester cisplatin, leading to a reduction in the levels of cisplatin–DNA damage. DNA is the therapeutic target of cisplatin, and efficacy is a function of cisplatin–DNA adducts inhibiting DNA replication and transcription, ultimately resulting in apoptosis. Reduced efficacy of the cisplatin is often observed in cells with increased GSH levels. Modulating the levels of intracellular thiols has been demonstrated to influence cisplatin cytotoxicity in numerous studies (3). In a report by Bratasz et al. (4) in a recent issue of PNAS, the authors exploited GSH overexpression using a nitric oxide (NO)-prodrug in a cisplatin-resistant ovarian cancer model to potentially counteract and target cisplatin-resistant cells.