Mechanisms of the Synergistic Interaction between the Bisphosphonate Zoledronic Acid and the Chemotherapy Agent Paclitaxel in Breast Cancer Cells in vitro

Abstract

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.

Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction

“…This includes a combination with paclitaxel (Jagdev et al, 2001;Neville-Webbe et al, 2006), tamoxifen (Jagdev et al, 2000) and doxorubicin (Neville-Webbe et al, 2005). In our earlier study with ZA and chemotherapy drugs, we have similarly found that sequential administration of drugs is of paramount importance for inducing maximal (potentially synergistic) levels of apoptosis.…”

“…Inhibition of the mevalonate pathway by nitrogen-bisphosphonates is integral for inducing a variety of effects including apoptosis of osteoclasts (Amin et al, 1992), breast cancer cells (Jagdev et al, 2001), prostate cancer cells (Oades et al, 2003), myeloma cells (Shipman et al, 1998) and inhibition of tumour cell invasion (Denoyelle et al, 2003). Furthermore, inhibition of this pathway also contributes to the apoptosis induced when breast (and prostate) cancer cells are treated in combination with ZA and doxorubicin (Neville-Webbe et al, 2005), or when breast cancer cells are treated with ZA and paclitaxel (Neville-Webbe et al, 2006).…”

Zoledronic acid use in cancer patients

“…21 Bisphosphonates also have demonstrated synergistic cytotoxic or cytostatic effects when administered in combination with chemotherapy agents. 17,[22][23][24][25][26][27][28][29][30][31][32][33] In human primary BC cells, concomitant exposure to ibandronate or ZOL plus cyclophosphamide combined with methotrexate and 5-fluorouracil or epirubicin combined with cyclophosphamide, paclitaxel, or docetaxel enhanced the cytostatic effects compared with chemotherapy alone. 31 In a murine model of human BC, ZOL alone reduced total tumor burden by 43% compared with placebo; moreover, ZOL plus doxycycline more effectively reduced bone tumor burden compared with doxycycline alone.…”

Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

“…Zoledronic acid has been shown to synergistically increase cancer cell death when combined with doxorubicin, paclitaxel, or cyclophosphamide in breast cancer cells (24)(25)(26); paclitaxel, etoposide, cisplatinum, and irinotecan in lung cancer cells (27); and dexamethasone in myeloma cells (28) in vitro. Combining zoledronic acid (250 μg/kg) with the oral fluoropyrimidine UFT (20 mg) daily decreased the number of bone metastases compared with single agents in the 4T1 mouse mammary tumor model (29).…”