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Na Kong, Xiaying Chen, Jiao Feng, Ting Duan, Shuiping Liu, Xueni Sun, Peng Chen, Ting Pan, Lili Yan, Ting Jin, Yu Xiang, Quan Gao, Chengyong Wen, Weirui Ma, Wencheng Liu, Mingming Zhang, Zuyi Yang, Wengang Wang, Ruonan Zhang, Bi Chen, Tian Xie, Xinbing Sui, Wei Tao. Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 4045-4054

Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1
Na Konga,c, Xiaying Chena,b, Jiao Fenga,b, Ting Duana,b, Shuiping Liua,b, Xueni Suna,b, Peng Chena,b, Ting Pana,b, Lili Yana,b, Ting Jina,b, Yu Xianga,b, Quan Gaoa,b, Chengyong Wena,b, Weirui Maa,b, Wencheng Liua,b, Mingming Zhanga,b, Zuyi Yanga,b, Wengang Wanga,b, Ruonan Zhanga,b, Bi Chena,b, Tian Xiea,b, Xinbing Suia,b, Wei Taoc
a. College of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, School of Medicine, Hangzhou Normal University, Hangzhou 311121, China;
b. Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China;
c. Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Abstract:
Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. Currently, the therapeutic role of ferroptosis on cancer is gaining increasing interest. Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types; however, the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown. In the study, we investigated the effect of baicalin on bladder cancer cells 5637 and KU-19-19. As a result, we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells. Subsequently, we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo, accompanied by reactive oxygen species (ROS) accumulation and intracellular chelate iron enrichment. The ferroptosis inhibitor deferoxamine but not necrostatin-1, chloroquine (CQ), N-acetyl-l-cysteine, l-glutathione reduced, or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK) rescued baicalin-induced cell death, indicating ferroptosis contributed to baicalin-induced cell death. Mechanistically, we show that ferritin heavy chain 1 (FTH1) was a key determinant for baicalin-induced ferroptosis. Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells. Taken together, our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis, which will hopefully provide a prospective compound for bladder cancer treatment.
Key words:    Baicalin    Ferroptosis    Bladder cancer    FTH1    Deferoxamine   
Received: 2021-02-01     Revised: 2021-03-07
DOI: 10.1016/j.apsb.2021.03.036
Funds: This work is supported by the grants National Natural Science Foundation of China (Nos. 81874380 and 82022075, to Xinbing Sui; 81730108 and 81973635, to Tian Xie), Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars (No. LR18H160001, to Xinbing Sui), Zhejiang Provincial Natural Science Foundation of China (Nos. LQ20H160013, Ting Duan; LQ21H160038, to Jiao Feng), and Zhejiang Province Science and Technology Project of TCM (Nos. 2019ZZ016, to Xinbing Sui; 2020ZQ046, to Ruonan Zhang, China).
Corresponding author: Tian Xie,E-mail:xbs@hznu.edu.cn;Xinbing Sui,E-mail:hzzju@hznu.edu.cn;Wei Tao,E-mail:wtao@bwh.harvard.edu     Email:xbs@hznu.edu.cn;hzzju@hznu.edu.cn;wtao@bwh.harvard.edu
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Authors
Na Kong
Xiaying Chen
Jiao Feng
Ting Duan
Shuiping Liu
Xueni Sun
Peng Chen
Ting Pan
Lili Yan
Ting Jin
Yu Xiang
Quan Gao
Chengyong Wen
Weirui Ma
Wencheng Liu
Mingming Zhang
Zuyi Yang
Wengang Wang
Ruonan Zhang
Bi Chen
Tian Xie
Xinbing Sui
Wei Tao

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