Feng Yuan, Zhou Jihong, Li Zhanhua, Jiang Ying, Zhou Ying
Department of Respiratory Medicine, Guangxi University of Traditional Chinese Medicine Affiliated Ruikang Hospital, NanNing, China.
Department of Neurology, Guangxi University of Traditional Chinese Medicine Affiliated Ruikang Hospital, NanNing, China.
PLoS One. 2016 Sep 14;11(9):e0162133. doi: 10.1371/journal.pone.0162133. eCollection 2016.
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.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）可选择性地作用于癌细胞。本临床前研究调查了首个小分子TRAIL诱导剂ONC201对肺癌细胞的抗癌效果。我们发现，ONC201对已建立的（A549和H460细胞系）及原代人肺癌细胞均具有细胞毒性和抗增殖作用。而对正常肺上皮细胞无细胞毒性。此外，ONC201可诱导肺癌细胞发生外源性凋亡激活，这可通过TRAIL/死亡受体-5（DR5）的诱导及半胱天冬酶-8的激活得以证明。半胱天冬酶-8抑制剂或TRAIL/DR5 siRNA敲低可减轻ONC201对肺癌细胞的细胞毒性。在分子水平上，ONC201可使肺癌细胞中的Akt-S6K1和Erk信号失活，导致叉头框蛋白O3a（Foxo3a）核转位。在体内研究中，以耐受性良好的剂量腹腔注射ONC201可显著抑制严重联合免疫缺陷（SCID）小鼠体内异种移植的A549肿瘤生长。此外，给予ONC201可诱导肿瘤组织中TRAIL/DR5表达，但使Akt-S6K1和Erk失活。该研究结果证明了ONC201具有强大的抗肺癌活性。
