YL4073 is a potent autophagy-stimulating antitumor agent in an in vivo model of Lewis lung carcinoma

Xu,You-Zhi; Li,Yong-Huai; Lu,Wen-Jie; Lu,Kun; Wang,Chun-Ting; Li,Yan; Lin,Hong-Jun; Kan,Li-Xin; Yang,Sheng-Yong; Wang,Si-Ying; Zhao,Ying-Lan

doi:10.3892/or.2016.4603

YL4073 is a potent autophagy-stimulating antitumor agent in an in vivo model of Lewis lung carcinoma

Authors:
- You-Zhi Xu
- Yong-Huai Li
- Wen-Jie Lu
- Kun Lu
- Chun-Ting Wang
- Yan Li
- Hong-Jun Lin
- Li-Xin Kan
- Sheng-Yong Yang
- Si-Ying Wang
- Ying-Lan Zhao
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Affiliations: School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Respiratory Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, Department of Electrocardiogram, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, P.R. China
Published online on: February 1, 2016 https://doi.org/10.3892/or.2016.4603
Pages: 2081-2088

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Abstract

Cancer cells activate autophagy in response to anticancer therapies. Autophagy induction is a promising therapeutic approach to treat cancer. In a previous study, YL4073 inhibited the growth of liver cancer and induced liver cancer cell apoptosis. Here, we demonstrated the anticancer activity and specific mechanisms of YL4073 in Lewis lung carcinoma LL/2 cells. Our results show that YL4073-induced autophagy was followed by apoptotic cell death. The anticancer and autophagy stimulating efficacy was confirmed by several factors, including the appearance of autophagic vacuoles, formation of acidic vesicular organelles, recruitment of microtubule-associated protein 1 light chain 3 II (LC3-II) to the autophagosomes, conversion and cleavage of LC3-I to LC3-II, upregulation of Beclin 1 expression, and formation of the Atg12-Atg5 conjugate in LL/2 cells after YL4073 treatment for 24 or 48 h. Furthermore, P53 activation and p-histone H3 phosphorylation occurred after cell exposure to YL4073 for 48 h, suggesting that cell apoptosis had occurred. Pharmacological inhibition of autophagy using 3-methyladenine increased cell apoptosis. Molecular level studies revealed that YL4073 inhibited survival signalling by blocking the activation of Akt and mTOR phosphorylation and reduced the expression of p-mTOR downstream targets for phosphorylation, including p70S6K, p-TSC, p-MAPK, and p-AMPK. This suggests that the Akt/mTOR/p70S6K and TSC/MAPK/AMPK pathways are involved in the effects of YL4073 treatment in LL/2 cells. In addition, YL4073 significantly inhibited LL/2 tumor growth and induced apoptosis in vivo. These data suggest that YL4073 has a significant anticancer effect, with a pathway-specific mechanism of autophagy both in vitro and in vivo.

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