PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation.
作者： Zhi-Xian Yin , Wei Hang , Gang Liu , Yi-Shu Wang , Xiang-Feng Shen
DOI: 10.18632/ONCOTARGET.21277
关键词:
摘要: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for with mutations gene although are responsive to surgery, irradiation, chemotherapy early treatment. p53-Reactivation Induction Massive Apoptosis-1 (PRIMA-1) its methylated analogue PRIMA-1Met (also known as APR-246) quinuclidine compounds that rescue DNA-binding activity mutant p53 (mut-p53) restore potential wild-type p53. In current report, we demonstrated inhibition poly (ADP-ribose) polymerase-1 (PARP-1) 6(5H)-phenanthridinone (PHEN) N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N, N-dimethylamino) acetamide hydrochloride (PJ34) sensitizes UMSCC1, UMSCC14, UMSCC17A, three lines treatment APR-246. PHEN enhances APR-246-induced apoptosis, but not programmed necrosis or autophagic death cells. The PARP-1 inhibition-induced sensitization cells APR-246 independent mutation. Instead, promotes APR-246-facilitated inactivation thioredoxin reductase 1 (TrxR1), leading ROS accumulation DNA damage. Overexpression TrxR1 application antioxidant N-acetyl-L-cysteine (NAC) depletes increase, reduces damage, decreases triggered by APR-246/PHEN Thus, have characterized a new function inhibitor elevation provide novel therapeutic strategy combination inhibitors
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