Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201.
Department of Respiratory Medicine, Guangxi University of Traditional Chinese Medicine Affiliated Ruikang Hospital, NanNing, China.
Yuan
Y
Feng
Department of Respiratory Medicine, Guangxi University of Traditional Chinese Medicine Affiliated Ruikang Hospital, NanNing, China.
Jihong
J
Zhou
Department of Respiratory Medicine, Guangxi University of Traditional Chinese Medicine Affiliated Ruikang Hospital, NanNing, China.
Zhanhua
Z
Li
Department of Neurology, Guangxi University of Traditional Chinese Medicine Affiliated Ruikang Hospital, NanNing, China.
Ying
Y
Jiang
Department of Oncology, Guangxi University of Traditional Chinese Medicine Affiliated Ruikang Hospital, NanNing, China.
Ying
Y
Zhou
D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D007093:Imidazoles; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D011494:Protein Kinases / Q000378:metabolism; D011725:Pyridines; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*
D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C585684:TIC10 compound; D011494:Protein Kinases