Cepharanthine, a regulator of keap1-Nrf2, inhibits gastric cancer growth through oxidative stress and energy metabolism pathway.

Autor: Lu YY; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Zhu CY; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Ding YX; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Wang B; Biomedical Centre, Qingdao University, Qingdao, China., Zhao SF; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Lv J; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Chen SM; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Wang SS; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Wang Y; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Wang R; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China., Qiu WS; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. wsqiuqd@163.com., Qi WW; Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. qwwqdfy@126.com.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2023 Dec 12; Vol. 9 (1), pp. 450. Date of Electronic Publication: 2023 Dec 12.
DOI: 10.1038/s41420-023-01752-z
Abstrakt: Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.
(© 2023. The Author(s).)
Databáze: MEDLINE
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