Tetrathiomolybdate induces doxorubicin sensitivity in resistant tumor cell lines

ObjectiveDoxorubicin is a potent anti-cancer agent with efficacy against a broad range of tumors, including endometrial cancer. Doxorubicin produces reactive oxygen species (ROS) resulting in cytotoxicity. Tetrathiomolybdate (TM), a copper-chelating agent, is known to target a cellular antioxidant enzyme copper/zinc-superoxide dismutase. This study tests the hypothesis that TM can modulate antioxidants in tumor cells and render doxorubicin resistant tumor cells sensitive to doxorubicin.MethodsThe anti-cancer activities of doxorubicin and TM, as single agents and in combination, were assessed. Flow cytometric and immunoblot analysis were conducted to investigate the induction of apoptosis and changes in apoptotic signaling pathways.ResultsDoxorubicin-induced growth inhibition was observed in each endometrial cancer cell line (ECC-1, AN3CA, and KLE) tested with cell specificity. ECC-1 and KLE cells were found to have increased resistance to doxorubicin than AN3CA cells. Moreover, doxorubicin mediated apoptosis was greater in the AN3CA cell line than ECC-1 and KLE. The combination of doxorubicin with a sub-cytotoxic level of TM was significantly more effective at inducing apoptosis in doxorubicin resistant cell lines.ConclusionOur results highlight the therapeutic potential of TM to sensitize tumor cells to doxorubicin for endometrial cancer treatment.

Research Highlights
► Copper-chelating agent tetrathiomolybdate induces sensitization of resistant endometrial cancer cells to doxorubicin.
► Reactive oxygen species generation and apoptotic MAPK activation correlates with the enhanced cytotoxicity of the tetrathiomolybdate/doxorubicin combination.