Synergistic effects of the PARP inhibitor olaparib and pharmacological ascorbate in castration-resistant prostate cancer

326 Background: The administration of ascorbate has proved lethal to and highly selective for a variety of cancer cell types; however, despite an increasingly impressive body of evidence, there has not been a robust effort to translate the observed in vitro and in vivo outcomes to the clinic. This is partially due to the fact that the mechanism by which ascorbate exerts its anti-cancer effect is still under investigation. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), by inhibiting DNA damage repair, would augment the toxicity of ascorbate. Methods: In vitro and in vivo models systems queried for anti-tumor effects of PARP inhibitors and ascorbate. Results: Two distinct castration-resistant prostate cancer (CRPC) models were sensitive to ascorbate at physiologically attainable concentrations. These in vitro models were then subjected to treatment with three different PARP inhibitors (olaparib, niraparib, and talazoparib) alone and in combination with ascorbate. The addition of a sub-lethal dose of ascorbate significantly increased cell death across a range of doses for all three PARP inhibitors. A combination index was generated for olaparib and ascorbate in both CRPC models; the results suggest a strongly synergistic relationship between olaparib and ascorbate. Use of a CRPC in vivo model demonstrated that the combination of olaparib and ascorbate significantly increased tumor doubling time compared to vehicle controls and monotherapy. This in vivo efficacy was even more profound in an additional model using castrated mice to mimic the effect of hormone therapy. Additional mechanistic studies are in progress to further investigate the potential for ascorbate and olaparib combination therapy. Conclusions: Ultimately, these data suggest the combination of ascorbate and PARP inhibitors could be an effective treatment for CRPC.