Abstract | BACKGROUND: RESULTS: Here, we report that reducing NADPH pools by genetically or pharmacologically (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) or CB-839) inhibiting glutamine metabolism in mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) PDA sensitizes cell lines and tumors to ß- lapachone (ß-lap, clinical form ARQ761). ß-Lap is an NADPH: quinone oxidoreductase (NQO1)-bioactivatable drug that leads to NADPH depletion through high levels of reactive oxygen species (ROS) from the futile redox cycling of the drug and subsequently nicotinamide adenine dinucleotide ( NAD)+ depletion through poly(ADP ribose) polymerase (PARP) hyperactivation. NQO1 expression is highly activated by mutant KRAS signaling. As such, ß-lap treatment concurrent with inhibition of glutamine metabolism in mutant KRAS, NQO1 overexpressing PDA leads to massive redox imbalance, extensive DNA damage, rapid PARP-mediated NAD+ consumption, and PDA cell death-features not observed in NQO1-low, wild-type KRAS expressing cells. CONCLUSIONS: This treatment strategy illustrates proof of principle that simultaneously decreasing glutamine metabolism-dependent tumor anti-oxidant defenses and inducing supra-physiological ROS formation are tumoricidal and that this rationally designed combination strategy lowers the required doses of both agents in vitro and in vivo. The non-overlapping specificities of GLS1 inhibitors and ß-lap for PDA tumors afford high tumor selectivity, while sparing normal tissue.
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Authors | Gaurab Chakrabarti, Zachary R Moore, Xiuquan Luo, Mariya Ilcheva, Aktar Ali, Mahesh Padanad, Yunyun Zhou, Yang Xie, Sandeep Burma, Pier P Scaglioni, Lewis C Cantley, Ralph J DeBerardinis, Alec C Kimmelman, Costas A Lyssiotis, David A Boothman |
Journal | Cancer & metabolism
(Cancer Metab)
Vol. 3
Pg. 12
( 2015)
ISSN: 2049-3002 [Print] England |
PMID | 26462257
(Publication Type: Journal Article)
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