Zoledronic acid / ATRA (all trans retinoic acid) combination enhances apoptosis in prostate cancer cell lines by down-regulating BIRC5 (survivin) mRNA expression

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Prostate cancer is the most commonly diagnosed cancer among men and with an estimated 41.000 Americans are dying annually from prostate cancer. Zoledronic acid (ZA) is the most potent nitrogen containing bisphosphonate compound widely used for treatment of bone metastases in prostate cancer patients. Moreover it inhibits cell growth and induces apoptosis in prostate cancer cell lines DU145, PC-3 and LNCaP. All Trans Retinoic Acid (ATRA), a natural analog of retinoids, is known for inducing apoptosis in various cancer cell lines.
 The objective of the study is to investigate the combinational effects of these agents in androgen-independent (PC-3 and DU-145) prostate cancer cell lines.
 Cytotoxicity were determined by colorimetric XTT assay. Rezasurin fluorescence intensity and Caspase-3, -7 activity were measured in the same wells by multiplexed assay. CalcuSyn software (Biosoft) was used to calculate combination index (CI) values based on the dose effect parameters for each agent alone and their fixed ratio combinations. The maximum cytotoxic doses were used for the investigation of apoptosis related genes by OligoGEArray technology from SuperArray since there is no available data in the literature.
 Zoledronic acid and ATRA combination were found to be synergistic in inducing both growth inhibition and apoptosis in prostate adenocarcinoma cells. These effects were paralleled by elevation of caspase-3 -7 activity and down regulation of BIRC-5/survivin gene that encodes BIRC5 protein which is known as the inhibitor of apoptosis by binding caspases and curtailing their activity.
 In conclusion, the combination of ZA and ATRA leads to enhanced antitumor activity at clinically achievable drug concentrations by down-regulating BIRC5 mRNA expression and inducing caspase activity and warrants further studies for clinical translation.