Inhibitory effect of hydnocarpin D on T-cell acute lymphoblastic leukemia via induction of autophagy-dependent ferroptosis |
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| Authors: | Siyue Lou Huanwu Hong Liwaliding Maihesuti Hang Gao Zhihui Zhu Lili Xu Shasha Tian Guoyin Kai Guozheng Huang Huajun Zhao |
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| Institution: | 1.College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; 2.Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China; 3.School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China; 4.College of Chemistry and Chemical Engineering, Anhui University of Technology, Ma’anshan 243002, China |
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| Abstract: | Hydnocarpin D (HD) is a bioactive flavonolignan compound that possesses promising anti-tumor activity, although the mechanism is not fully understood. Using T cell acute lymphoblastic leukemia (T-ALL) cell lines Jurkat and Molt-4 as model system, we found that HD suppressed T-ALL proliferation in vitro, via induction of cell cycle arrest and subsequent apoptosis. Furthermore, HD increased the LC3-II levels and the formation of autophagolysosome vacuoles, both of which are markers for autophagy. The inhibition of autophagy by either knockdown of ATG5/7 or pre-treatment of 3-MA partially rescued HD-induced apoptosis, thus suggesting that autophagy enhanced the efficacy of HD. Interestingly, this cytotoxic autophagy triggered ferroptosis, as evidenced by the accumulation of lipid ROS and decrease of GSH and GPX4, while inhibition of autophagy impeded ferroptotic cell death. Our study suggests that HD triggers multiple cell death processes and is an interesting compound that should be evaluated in future preclinical studies. |
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| Keywords: | Hydnocarpin D T-ALL apoptosis ferroptosis autophagy |
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