Additive/synergistic antitumoral effects on prostate cancer cells in vitro following treatment with a combination of docetaxel and zoledronic acid

Abstract

Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden Abstract Once bone metastasized and androgen independent, prostate cancer is often associated with skeletal morbidity and disability. New treatment modalities that can palliate symptoms from the skeleton and inhibit further progression are warranted. In this study, the antitumoral effects following treatment with a combination of docetaxel and the new generation bisphosphonate, zoledronic acid, were investigated on two hormone-refractory prostate cancer cell lines: PC3 and DU145. The prostate cancer cells were treated with increasing concentrations of zoledronic acid in the absence or presence of docetaxel. Toxicity was measured using fluorometric microculture cytotoxic assay technique. A concentration of 25 mM, zoledronic acid reduced the viable cell number to 68% and 98% for PC3 and DU145 cells respectively. Docetaxel, on the other hand, at a concentration of 0.1 ng/ml, had no effect on the viability. However, a combination of zoledronic acid and docetaxel reduced the cell number to 60% and 81% respectively. Furthermore, zoledronic acid in the concentration range 12.5 mM Á/50 mM enhanced the antitumoral effects of docetaxel (0.01 Á/1 ng/ml) in an additive and/or synergistic manner for both cell lines. These data support the hypothesis that zoledronic acid, in addition to having bone resorption inhibiting properties, also exhibits anti-tumoral effects. It also appears that combined treatment with docetaxel causes additive and/or synergistic cytostatic effects on prostate cancer cells.

Guidelines for the management of castrate-resistant prostate cancer

“…Zoledronic acid has been used safely with a variety of cytotoxic chemotherapies in clinical trials. 31 Adverse events reported during bisphosphonate treatment did not appear to increase with concomitant chemotherapy.…”

Current Management of Castrate-Resistant Prostate Cancer

“…In clinical trials, zoledronic acid has been used safely with a variety of cytotoxic chemotherapies; preclinical data suggest that docetaxel and zoledronic acid may have additive or synergistic effects on pca cells 43 . Adverse events reported during bisphosphonate treatment did not appear to increase with concomitant chemotherapy.…”

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

“…16,17 In preclinical testing, zoledronic acid has been shown to be the most potent inhibitor of bone resorption compared to other bisphosphonates 18 and this potency is also reflected in the various antitumor activities investigated to date. Furthermore, zoledronic acid has shown synergistic induction of cancer cell apoptosis in vitro when combined with a variety of agents, e.g., with imatinib mesylate in leukemia cells 19 or in lung cancer cells, 20 with gemcitabine in prostate cancer cells, 21 with paclitaxel or tamoxifen 22,23 or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 24 in breast cancer cells and with dexamethasone in myeloma cells. 25 Other bisphosphonates investigated for synergistic cell death in combination with chemotherapeutic agents have shown either no effect (pamidronate with DTIC in melanoma cell lines) 26 or additive activity at best (ibandronate with taxanes in breast cancer cells).…”