Effect of tamoxifen on mitoxantrone cytotoxicity in drug-sensitive and multidrug-resistant MCF-7 cells

Abstract

The influence of the antiestrogen tamoxifen (TAM) on the activity of mitoxantrone (MXN), was evaluated against wild-type MCF-7/WT and their multidrug-resistant variant MCF-7/ADR cells. Multidrug resistance (MDR) in this cell line which was selected for resistance to Adriamycin (ADR), is associated with increased expression of P-glycoprotein (P-gp). In a clonogenic assay it was observed that TAM (1-10 microM) significantly enhanced the activity of MXN in the MCF-7/ADR but not in the drug-sensitive cell line. Isobologram analysis indicated that the effect of the combination was additive in the parental MCF-7/WT cells and strongly synergistic in the MDR MCF-7/ADR cells. Also, TAM (10 microM) caused a three-fold increase in the steady-state levels (Css) of MXN in MCF-7/ADR cells but did not modulate MXN levels in MCF-7/WT cells. The observed synergism in MCF-7/ADR cells was perhaps due to the increase in Css of MXN that may involve interaction of TAM with P-gp. The combination of MXN and TAM may be useful in the treatment of drug-sensitive and drug-resistant breast cancer.