Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1

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

doi:10.1016/j.apsb.2021.03.036

Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1

Acta Pharm Sin B. 2021 Dec;11(12):4045-4054. doi: 10.1016/j.apsb.2021.03.036. Epub 2021 Mar 27.

Authors

Na Kong^{1

2}, Xiaying Chen^{1

3}, Jiao Feng^{1

3}, Ting Duan^{1

3}, Shuiping Liu^{1

3}, Xueni Sun^{1

3}, Peng Chen^{1

3}, Ting Pan^{1

3}, Lili Yan^{1

3}, Ting Jin^{1

3}, Yu Xiang^{1

3}, Quan Gao^{1

3}, Chengyong Wen^{1

3}, Weirui Ma^{1

3}, Wencheng Liu^{1

3}, Mingming Zhang^{1

3}, Zuyi Yang^{1

3}, Wengang Wang^{1

3}, Ruonan Zhang^{1

3}, Bi Chen^{1

3}, Tian Xie^{1

3}, Xinbing Sui^{1

3}, Wei Tao²

Affiliations

¹ College of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, School of Medicine, Hangzhou Normal University, Hangzhou 311121, China.
² Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ 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.

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.

Keywords: Baicalin; Bladder cancer; Deferoxamine; FTH1; Ferroptosis.