Novobiocin sensitizes BCRP/MXR/ABCP overexpressing topotecan-resistant human breast carcinoma cells to topotecan and mitoxantrone.

Background: Novohiocin was shown to sensitize cancer cells to etoposide and alkylating agents. Human breast carcinoma cells exposed to topotecan (MCF7/TPT300 cells) developed resistance to both mitoxantrone and topotecan. An ATP-binding cassette family protein BCRP/MXR/ABCP was overexpressed in MCF7/TPT300 cells. In addition, topotecan efflux was markedly enhanced in the resistant cells. To investigate the possibility that novohiocin may enhance cytotoxicity in BCRP/MXR/ABCP overexpressing cells, we exposed MCF7/TPT300 cells to novohiocin. Materials and Methods: Cytotoxicity tests of topotecan and mitoxantrone, as well as topotecan accumulation tests, were performed with or without novobiocin in MCF7/TPT300 cells. Results: Novobiocin enhances topotecan and mitoxantrone toxicity in MCF7/TPT300 cells at a clinically relevant concentration. Novobiocin enhanced cellular accumulation of topotecan and inhibited topotecan efflux in MCF7/TPT300 cells. Conclusion: Novohiocin may enhance topotecan and mitoxantrone toxicity in topotecan-resistant breast carcinoma cells. Novohiocin may be useful to reverse topotecan or mitoxantrone resistance in the clinic.