Abstract B08: Triptolide has antitumor effects in lung cancer via Wnt pathway inhibition.

Abstract

Abstract Introduction: Triptolide is an extract of the herb Tripterygium wilfordii (Tw), which has been used to treat autoimmune disorders in traditional Chinese medicine. It has also been reported to have anti-cancer effects in vitro, although little is known about its mechanism of action. The Wnt/B-catenin pathway has been implicated in regulating cancer stem cells in lung cancer, making this pathway a potential target for novel lung cancer therapies. Methods: Here we tested the efficacy of triptolide in several lung cancer cell lines. We elucidated a Wnt pathway mechanism for triptolide effect in lung cancer, first by using a Wnt focused cDNA array in vitro. We examined the effect of triptolide on tumor cell death using flow cytomotery and a beta-galactosidase assay. We tested the ability of triptolide to prevent development of lung tumors in the E160D transgenic mouse model of lung cancer, which carries a somatic mutation in the DNA repair enzyme flap endonuclease-1 (FEN-1). Twelve month old mice were fed triptolide 1mg/kg daily for 2 months and were sacrificed at 18 months along with a control group. Results: Triptolide had more potent therapeutic efficacy in multiple lung cancer cell lines compared with cisplatin and paclitaxel, in vitro. In H460 and A549 cell lines, we found that triptolide resulted in Wnt pathway silencing via overexpression of Wnt inhibitory factor-1 (WIF-1), which occurs due to promoter demethylation. Addition of recombinant Wnt3a, which causes Wnt pathway activation, partially rescues the effect of triptolide on lung cancer cell lines. Triptolide resulted in cellular senescence as demonstrated by beta-galactosidase assay. Finally, in the E160D transgenic mouse model of lung cancer, a two month course of oral triptolide treatment decreased the development of lung tumors from 70% to 30% at 18 months (p=0.01). There were no observed clinical toxicities at the dosage of triptolide used. Conclusions: Triptolide has potent anti-cancer effects in vitro in lung cancer cell lines, and significantly decreases lung tumor development in a transgenic mouse model. Triptolide suppresses the Wnt pathway by causing upregulation of WIF-1a by promoter demethylation. Future studies are needed to test this promising and novel Wnt-targeting therapy in lung cancer animal models, and to identify biomarkers which may predict sensitivity in particular subgroups of lung cancer patients. Citation Format: Youqiang Li, Li Zheng, Binghui Shen, Jae Kim, Dan Raz. Triptolide has antitumor effects in lung cancer via Wnt pathway inhibition. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B08.