Baicalein triggers ferroptosis in colorectal cancer cells via blocking the JAK2/STAT3/GPX4 axis.

Autor: Lai JQ; Department of General Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510630, China.; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.; Department of General Surgery, Guangzhou First People's Hospital, Guangzhou, 510180, China., Zhao LL; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China., Hong C; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.; College of Pharmacy, Jinan University, Guangzhou, 510632, China., Zou QM; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China., Su JX; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China., Li SJ; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China., Zhou XF; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China., Li ZS; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China., Deng B; The Affiliated Shunde Hospital of Jinan University, Foshan, 528305, China. gzyybird@aliyun.com., Cao J; Department of General Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510630, China. eycaojie@scut.edu.cn.; Department of General Surgery, Guangzhou First People's Hospital, Guangzhou, 510180, China. eycaojie@scut.edu.cn., Qi Q; State Key Laboratory of Bioactive Molecules and Drug ability Assessment; MOE Key Laboratory of Tumor Molecular Biology; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China. qiqikc@jnu.edu.cn.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China. qiqikc@jnu.edu.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Aug; Vol. 45 (8), pp. 1715-1726. Date of Electronic Publication: 2024 Apr 29.
DOI: 10.1038/s41401-024-01258-z
Abstrakt: Colorectal cancer (CRC) is a prevalent form of gastrointestinal malignancy with challenges in chemotherapy resistance and side effects. Effective and low toxic drugs for CRC treatment are urgently needed. Ferroptosis is a novel mode of cell death, which has garnered attention for its therapeutic potential against cancer. Baicalein (5, 6, 7-trihydroxyflavone) is the primary flavone extracted from the dried roots of Scutellaria baicalensis that exhibits anticancer effects against several malignancies including CRC. In this study, we investigated whether baicalein induced ferroptosis in CRC cells. We showed that baicalein (1-64 μM) dose-dependently inhibited the viability of human CRC lines HCT116 and DLD1. Co-treatment with the ferroptosis inhibitor liproxstatin-1 (1 μM) significantly mitigated baicalein-induced CRC cell death, whereas autophagy inhibitor chloroquine (25 μM), necroptosis inhibitor necrostatin-1 (10 μM), or pan-caspase inhibitor Z-VAD-FMK (10 μM) did not rescue baicalein-induced CRC cell death. RNA-seq analysis confirmed that the inhibitory effect of baicalein on CRC cells is associated with ferroptosis induction. We revealed that baicalein (7.5-30 μM) dose-dependently decreased the expression levels of GPX4, key regulator of ferroptosis, in HCT116 and DLD1 cells by blocking janus kinase 2 (JAK2)/STAT3 signaling pathway via direct interaction with JAK2, ultimately leading to ferroptosis in CRC cells. In a CRC xenograft mouse model, administration of baicalein (10, 20 mg/kg, i.g., every two days for two weeks) dose-dependently inhibited the tumor growth with significant ferroptosis induced by inhibiting the JAK2/STAT3/GPX4 axis in tumor tissue. This study demonstrates that ferroptosis contributes to baicalein-induced anti-CRC activity through blockade of the JAK2/STAT3/GPX4 signaling pathway, which provides evidence for the therapeutic application of baicalein against CRC.
(© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
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