PARP-inhibitor/nitric oxide (NO)-donor dual prodrugs as anticancer agents

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	BIOCHEM/CHEM-22

Authors

• JE Saavedra
• WS Sehareen
• L Shi
• LW Fornwald
• RK Prud'homme
• LK Keefer
• AE Maciag

Abstract

Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based cancer therapeutics. Poly(ADP-ribose) polymerase (PARP) is an attractive antitumor target because of its vital role in DNA repair. PARP inhibitors have advanced into clinical trials, as single agents in specific patient populations or combination therapies with various chemotherapeutics. We have synthesized JS-60-178, a diazeniumdiolate-based NO-releasing/PARP inhibitor-dual prodrug, which combines DNA-damaging NO with the structural features of olaparib, a DNA repair-blocking PARP inhibitor. NO prodrugs of this class are activated in the cell by glutathione (GSH) in the reaction accelerated by glutathione S-transferase (GST). High levels of GSH/GST are often a feature of cancer cells. Therefore, the prodrug approach allowing concurrent release of cytotoxic components upon metabolic activation in the cancer cell should have advantages over delivering two independent molecules. JS-60-178 showed superior cytotoxic activity against non-small cell lung cancer (NSCLC) cells in vitro compared to olaparib. Treatment led to DNA damage, activation of stress signaling pathways and apoptosis. The in vitro effectiveness correlated with the high levels of the cancer cells’ endogenous reactive oxygen species (ROS), as well as levels of antioxidant defenses and DNA repair mechanisms. Cellular pathways involved and in vivo efficacy are under study.

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