PARP inhibition and pharmacological ascorbate demonstrate synergy in castration-resistant prostate cancer

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. While organ-confined disease has a reasonable expectation of cure, metastatic PCa is universally fatal upon recurrence during hormone therapy, a stage termed castration-resistant prostate cancer (CRPC). Until such time as molecularly defined subtypes can be identified and targeted using precision medicine, it is necessary to investigate new therapies that may apply to the entire CRPC population. The use of ascorbate, more commonly known as ascorbic acid or Vitamin C, has demonstrated antitumor activity in a variety of cancer cell types. There are several mechanisms currently under investigation to explain how ascorbate exerts anticancer effects. 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, by inhibiting DNA damage repair, would augment the toxicity of ascorbate, leading to improved antitumor effects. Two distinct CRPC models were found to be sensitive to physiologically relevant doses of ascorbate. Moreover, additional studies indicate that ascorbate inhibits CRPC growth in vitro via multiple mechanisms including disruption of cellular energy dynamics and accumulation of DNA damage. Combination studies were performed in CRPC models with ascorbate in conjunction with escalating doses of three different PARP inhibitors (niraparib, olaparib, and talazoparib). The addition of ascorbate augmented the toxicity of all three PARP inhibitors and proved synergistic effects with olaparib in both CRPC models. Finally, the combination of olaparib and ascorbate was tested in vivo in both castrated and noncastrated models. In both cohorts, the combination treatment significantly delayed tumor growth compared to monotherapy or untreated control. These data indicate that pharmacological ascorbate is an effective monotherapy at physiological concentrations and kills CRPC cells. Ascorbate-induced tumor cell death was associated with disruption of cellular energy dynamics and accumulation of DNA damage. The addition of PARP inhibition increased the extent of DNA damage and proved effective at slowing CRPC growth both in vitro and in vivo. These findings implicate ascorbate and PARPi as a novel therapeutic regimen that has the potential to improve CRPC patient outcomes.