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Elevated expression of <jats:underline>N<\/jats:underline>AD(P)H:<jats:underline>q<\/jats:underline>uinone oxidoreductase 1 (NQO1) is frequent in pancreatic cancer, and it offers promising tumor-selective targeting. Recently, KP372-1 was identified as a novel NQO1 redox cycling agent that induces cytotoxicity in cancer cells by creating redox imbalance; however, the mechanistic basis of KP372-1-induced cytotoxicity remains elusive. Here, we show that KP372-1 sensitizes NQO1-expressing pancreatic cancer cells and spares immortalized normal pancreatic duct cells, hTERT-HPNE. Notably, we found that KP372-1 is ~\u200910- to 20-fold more potent than \u03b2-lapachone, another NQO1 substrate, against pancreatic cancer cells. Mechanistically, our data strongly suggest that reactive oxygen species produced by NQO1-dependent redox cycling of KP372-1 cause robust DNA damage, including DNA breaks. Furthermore, we found that KP372-1-induced DNA damage hyperactivates the central DNA damage sensor protein poly(ADP-ribose) polymerase 1 (PARP1) and activates caspase-3 to initiate cell death. Our data also show that the combination of KP372-1 with PARP inhibition creates enhanced cytotoxicity in pancreatic cancer cells. Collectively, our study provides mechanistic insights into the cytotoxicity instigated by KP372-1 and lays an essential foundation to establish it as a promising chemotherapeutic agent against cancer.<\/jats:p>","DOI":"10.1038\/s41598-020-76850-4","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T11:03:51Z","timestamp":1605783831000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["DNA damage induced by KP372-1 hyperactivates PARP1 and enhances lethality of pancreatic cancer cells with PARP inhibition"],"prefix":"10.1038","volume":"10","author":[{"given":"Talysa","family":"Viera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen L.","family":"Patidar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,19]]},"reference":[{"key":"76850_CR1","doi-asserted-by":"publisher","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","volume":"74","author":"L Rahib","year":"2014","unstructured":"Rahib, L. et al. 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