Ketotifen reverses MDR1-mediated multidrug resistance in human breast cancer cells in vitro and alleviates cardiotoxicity induced by doxorubicin in vivo.

Abstract

To investigate the effect of the antihistamine ketotifen on multidrug resistance in human breast cancer cells and doxorubicin toxicity in mice. Clonogenicity assays were used to test the effect of ketotifen on human multidrug resistant breast cancer cell lines exposed to chemotherapeutic agents. Flow cytometry was used to measure accumulation of doxorubicin in cells. Fluorimetry was used to measure accumulation of doxorubicin in cardiac tissues. Histological analysis and toxicity studies in mice were used to test the effect of ketotifen on doxorubicin-induced toxicity. Ketotifen was found to restore the sensitivity of P-glycoprotein-overexpressing multidrug-resistant MCF-7/adr cells to doxorubicin, mitoxantrone, VP-16 and vinblastine, but not to methotrexate or camptothecin. Ketotifen, however, was unable to restore sensitivity of BCRP-overexpressing MCF-7/mx cells or MRP-overexpressing MCF-7/vp cells to mitoxantrone or VP-16, respectively. In vivo, pretreatment of mice with ketotifen caused an increased accumulation of doxorubicin in cardiac tissue, consistent with a block in drug clearance. However, unlike verapamil, ketotifen pretreatment did not enhance doxorubicin toxicity but in fact provided protection, both at the level of cardiac tissue damage and in terms of survival. Taken together, these observations show that ketotifen is unique in its ability both to reverse multidrug resistance due to P-glycoprotein overexpression and to provide cardioprotection to doxorubicin.