Multidrug resistance (MDR) is a major obstacle to chemotherapeutic cancer treatments. MDR is often a result of up-regulation of ATP-binding cassette (ABC) transporters following chemotherapy, one example being the multidrug pump P-glycoprotein (P-gp). We have been exploring the phenomenon of collateral sensitivity (CS) � the ability of some compounds to selectively kill MDR cancer cells over non-MDR cancer cells. Three topics will be discussed. (1) The isatin-�-thiosemicarbazone NSC73306 was shown to selectively kill P-gp expressing cells. Structure-activity studies have revealed the key pharmacophore required for activity. (2) The orphan drug tiopronin was unexpectedly found to mediate CS, but in a non-P-gp dependent manner. We have determined that the CS activity of tiopronin is mediated by generation of reactive oxygen species (ROS), achieved by inhibition of the enzyme glutathione peroxidase (GPx). (3) A high-throughput screen has been developed, and identified several new CS leads.

Resistance is useless: Structure-activity and mechanistic studies of small molecules that induce collateral sensitivity in multidrug-resistant cancer cells

245th National Meeting (2013)

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