Mechanisms of apoptosis and cell-cycle arrest in subcutaneous breast tumours treated sequentially with doxorubicin followed by zoledronic acid

Breast cancer patients commonly receive a combination of different therapies; for patients with late-stage breast cancer involving metastasis to the bone, a chemotherapeutic agent is usually given in combination with the antiresorptive drug zoledronic acid (zol) (Novartis Pharma, Basel, Switzerland). We have previously reported that administration of doxorubicin (dox) (Pharachemie BV, Haarlem, The Netherlands) 24 hours prior to zol inhibits subcutaneous breast tumour growth, inhibits tumour cell proliferation and increases apoptosis in vivo. The aims of the present study were to determine the mechanisms by which dox and zol exert their synergistic antitumour effects.