NQO1-Bioactivatable Drugs at the Interface of Cancer Metabolism and the DNA Damage Response

Increased levels of reactive oxygen species (ROS) have been observed in multiple cancer types, where they are crucial for tumor biology. Concomitantly, tumor cells also have enhanced expression of antioxidant pathway proteins to detoxify excess ROS. Thus, a challenge for anti-cancer therapeutics is to fine-tune this delicate balance from ROS protection, to ROS production while sparing normal tissue from toxicity. The phase II detoxification enzyme, NAD(P)H:quinone oxidoreductase-1, NQO1, is dramatically overexpressed in many solid tumor types, including pancreatic ductal adenocarcinoma (PDA) and non-small cell lung cancer (NSCLC). The Boothman laboratory has demonstrated that NQO1 bioactivates a unique class of quinones, such as ß-lapachone (ß-lap) and deoxyniboqunine (DNQ), through a futile redox cycle to generate massive levels of superoxide radical to induce extensive DNA oxidative base damage, single strand breaks and poly(ADP-ribose) polymerase 1 (PARP1)-driven depletion of intracellular NAD+. However, tumor cell NADPH and glutathione (GSH) biogenesis can attenuate the efficacy of this class of drugs by blunting the ROS formation produced from the futile redox cycle. Therefore, it is increasingly important to identify and target tumor specific antioxidant defenses to sensitize cancer cells, but not normal tissue, to NQO1 bioactivatable drugs. The data presented in the first half of this dissertation demonstrate that targeting glutamine dependent transamination reactions depletes antioxidant defenses in PDA and sensitizes tumors, but not normal tissue, to ß-lap-induced programmed necrosis in vitro and in vivo. Downstream of ROS formation, another mechanism by which tumors can attenuate ß-lap efficacy is through the repair of DNA lesions, specifically through base excision repair (BER). The latter half of this thesis focuses on inhibiting BER in combination with ß-lap as a mechanism to drive PARP1 hyperactivation and synergistic killing of NQO1-expressing PDA, but not associated normal tissue.

Author dc:creator

• Chakrabarti, Gaurab

Contributors dc:contributor

• Burma, Sandeep
• Brekken, Rolf A.
• DeBerardinis, Ralph J.
• Boothman, David A.

• DNA Repair
• NAD(P)H Dehydrogenase (Quinone)
• Neoplasms

Language dc:language

en

Identifier

988778239

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/4133