Causing DNA damage and stopping DNA repair - Vitamin D supplementation with Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors may cause selective cell death of cancer cells: A novel therapeutic paradigm utilizing elevated copper levels within the tumour.

Inhibitors of PARP1 are currently being used to treat malignancies and as maintenance drugs post chemotherapy. Vitamin D has been shown to have an anticancer effect (mediated by multiple mechanisms) and is usually deficient in cancer patients. We had previously proposed and experimentally validated the selective cell death of cancer cells caused due to interaction of vitamin D with elevated copper within malignant cells, leading to ROS mediated DNA damage. In this communication we propose a Vitamin D supplementation strategy with PARP1 inhibitor treatment which would have multifaceted benefits for therapy. Besides exerting its anticancer effects by other mechanisms and addressing the deficiency, Vitamin D in principle would cause selective ROS mediated DNA breakage in malignant cells, while sparing healthy non malignant cells. Since Vitamin D is also a known inhibitor of PARP1, this therapeutic strategy would push the malignant cells to apoptosis due to DNA breakage via the vitamin D-copper mechanism, in addition to inhibiting DNA repair. Since the available levels copper within normal cells are several fold less as compared to malignant cells, the normal cells would be spared of the Vitamin D induced, ROS mediated DNA damage and would be less likely to die due to PARP1 inhibition.

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