Toxicol Appl Pharmacol. 2019 Feb 15;365:1-8. doi: 10.1016/j.taap.2019.01.002. Epub 2019 Jan 2.
Zhang M1, Tan S1, Yu D2, Zhao Z1, Zhang B1, Zhang P1, Lv C1, Zhou Q3, Cao Z4.
Author Information
1Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, 2011 Collaborative Innovation Center of Hematology, Soochow University; Suzhou, Jiangsu 215123, PR China.
2Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China.
3Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, 2011 Collaborative Innovation Center of Hematology, Soochow University; Suzhou, Jiangsu 215123, PR China. Electronic address: zhouqs@suda.edu.cn.
4Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, 2011 Collaborative Innovation Center of Hematology, Soochow University; Suzhou, Jiangsu 215123, PR China. Electronic address: zhfcao@suda.edu.cn.
Abstract
Lung cancer is a leading lethal disease with a 5-year survival rate of only 16%. Inadequate potent anti-cancer drugs appear to be a bottleneck in the treatment of lung cancer; hence, how to develop effective anti-lung cancer therapeutics is an urgent problem. In this study, we aim to explore a novel compound with potent anti-lung cancer effect and study its anti-cancer mechanisms. We found that triptonide at very low concentrations of 5-10?nM caused a marked suppression of cell proliferation and colony formation of lung cancer cells. More interestingly, triptonide also robustly inhibited the lung cancer cell formation of tumor spheres, and reduced the stemness and tumorigenicity of the sphere-forming cells. In vivo studies showed that administration of triptonide significantly inhibited the tumor growth with low toxicity. Molecular mechanistic studies revealed that triptonide significantly decreased expression of the Gli1 at both mRNA and protein levels by repressing Gli1 gene promoter activity. Additionally, triptonide reduced the levels of cancer stem cell key signaling protein sonic hedgehog (Shh), but increased the amount of Ptch1, a protein binding to SMO to diminish the Shh signal transduction, thus inhibition of the Shh-Gli1 signaling pathway. Together, our findings show that triptonide effectively inhibits lung cancer cell growth, stemness, and tumorigenicity, and support the notion that triptonide is a new Shh-Gli1 signaling inhibitor and a novel anti-lung cancer drug candidate for further developing effective lung cancer therapeutics.