Organoruthenium Complexes with Benzo-Fused Pyrithiones Overcome Platinum Resistance in Ovarian Cancer Cells

SIMPLE SUMMARY: Ovarian cancer is the fifth most common cancer in the developing world, with many front-line treatments combining paclitaxel with platinum-based anticancer agents cisplatin/carboplatin. However, increased incidence of platinum resistance demands the development of new chemotherapeutic agents. The aim of our study was to explore a new family of organoruthenium(II) pyrithione complexes for their efficacy towards platinum-resistant ovarian cancer cells. We confirmed that this new class of compounds remain highly potent towards platinum-insensitive cells and appear to work by a mechanism that is not common to platinum agents. ABSTRACT: Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G(1) cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes.