Chemotherapy: Open Access
Open Access

Abstract

Tumor-Specific Induction of Oxidative Stress with Dichloroacetate and Auranofin May Complement the Efficacy of PARP Inhibition in Cancer Control

Mark F. Mc Carty

PARP inhibition can improve survival in cancer patients whose tumors have impaired capacity for homologous recombination, such as germ line or somatic mutations in BRCA. The efficacy of such therapy should be greater if the rate at which cancer cell DNA incurs single-strand breaks is enhanced. Since oxidative stress promotes formation of such breaks, measure which boost oxidative stress in cancer ? preferable somewhat selectively ? may be worthwhile adjuvants to PARP therapy. In the many cancers that express the Warburg phenomenon, dichloroacetate can promote increased mitochondrial generation of oxidants by directing more pyruvate to oxidation in the Krebs cycle. Concurrent administration of the arthritis drug auranofin could further enhance mitochondrial release of hydrogen peroxide by indirectly inhibiting peroxiredoxin-3, the chief mitochondrial source of peroxidase activity. The copper-chelating drug tetrathiomolybdate, employed in cancer therapy as an anti-angiogenic agent, can boost superoxide levels by diminishing activity of the copper-zinc-dependent cytosolic superoxide dismutase. Episodic intravenous infusion of high-dose ascorbate could also be employed to increase oxidative stress in the cancer and thereby complement PARP inhibitor therapy. The potential of dichloroacetate, auranofin, tetrathiomolybdate, and intravenous ascorbate to enhance the cancer-retardant efficacy of olaparib (or other PARP inhibitors) could be assessed in cell culture and rodent models.