FIGURE 1.

PARP inhibitors switch cell death to apoptosis from programmed necrosis. (A) NOQ1 bioactivatable drug β-lap mediates a futile redox cycle with NQO1 detoxifying enzyme, creating a large pool of NAD⁺ and hydrogen peroxide. Hydrogen peroxide formation leads to the formation of oxidized bases and SSBs that induces PARP1 hyperactivation. PARP1 utilizes NAD⁺ for activity, which depletes NAD⁺ and ATP, resulting in NAD⁺-Keresis. (B) Addition of PARP inhibitor prevents PARP1 hyperactivation and spares ATP and NAD⁺. Cellular processes can then recycle NAD⁺ back to NAD(P)H, which power more turns of the futile cycle creating even more oxidized bases and SSBs. PARP1 inhibition results in SSB-to-DSB conversion and death by apoptosis.