Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro.

Breast cancer patients often receive both paclitaxel and zoledronic acid as part of their treatment, and these drugs are reported to have synergistic effects on the induction of apoptosis of breast cancer cells in vitro. We have found that the synergistic interaction is drug sequence dependent, with maximal levels of apoptosis achieved when cells are treated with paclitaxel followed by zoledronic acid, as opposed to the reverse sequence or simultaneous treatment. The synergistic interaction persists at clinically relevant concentrations and incubation periods. We report that the sequential treatment is associated with cell cycle changes and depends on breast cancer cell characteristics, with hormone independence, mutated p53 status and presence of BRCA1 gene being associated with higher levels of apoptosis. Finally, we have found that the synergistic induction of apoptosis is via zoledronic acid-mediated inhibition of the mevalonate pathway.