Pretreatment of breast cancer cells with doxorubicin facilitates the subsequent uptake of zoledronic acid

Breast cancer patients commonly receive a combination of different therapies; however, our understanding of how such combined treatments work is incomplete. We have previously shown that sequential administration of the cytotoxic agent doxorubicin (dox) (Pharmachemie BV, Haarlem, The Netherlands) followed by the antiresorptive agent zoledronic acid (zol) (Novartis Pharma, Basel, Switzerland) synergistically increased tumour cell apoptosis in vitro, and also increased tumour cell apoptosis, decreased tumour cell proliferation and reduced subcutaneous in breast tumour growth in vivo. In contrast, pretreating the cells with zol before dox or adding both drugs simultaneously did not cause synergy. The aim of the present study was to determine the mechanism by which sequential administration of dox followed by zol exerts the increased antitumour effects.