Anti-pancreatic cancer activity of cassane diterpenoids isolated from the seeds of Caesalpinia sappan mediated by autophagy activation via ROS/AMPK/mTORC1 pathway.

Autor: Su J; School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, 650500, PR China., Wang DS; Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650504, PR China; School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, PR China., Hu GX; School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, 650500, PR China., Liu YY; School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, 650500, PR China., Hu M; Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650504, PR China., Chen Y; School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, 650500, PR China., Wang QQ; School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, 650500, PR China., Yan RC; Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650504, PR China., Wu Y; Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650504, PR China., Li YJ; Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650504, PR China., Ma K; Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, 650011, PR China., Qi YY; Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650504, PR China. Electronic address: Qiyanyan107@163.com., Ding LF; School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, PR China; College of Modern Biomedical Industry, Kunming Medical University, Kunming, 650500, PR China. Electronic address: dinglinfen@kmmu.edu.cn., Wu XD; Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650504, PR China. Electronic address: wuxingdeymu@163.com.
Jazyk: angličtina
Zdroj: Phytochemistry [Phytochemistry] 2024 Jun; Vol. 222, pp. 114105. Date of Electronic Publication: 2024 Apr 23.
DOI: 10.1016/j.phytochem.2024.114105
Abstrakt: Three undescribed cassane diterpenoids, caesalpanins D-F (1-3), and seven known ones were isolated from the seeds of Caesalpinia sappan. Structures and absolute configurations of 1-3 were elucidated based on the extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. Structurally, compound 1 was the first example of 18-norcassane diterpenoid and 2 was a rare 20-norcassane diterpenoid having an unusual five-membered oxygen bridge between C-10/C-18. The anti-proliferative activity of 1, 3, and 4-10 against PANC-1 cells (pancreatic ductal adenocarcinoma cell line) was evaluated, and phanginin H (4) was found to exhibit anti-cancer activity with IC 50 value of 18.13 ± 0.63 μM. Compound 4 inhibited PANC-1 cell growth by arresting the cell cycle at G2/M phase via regulation of cyclin-dependent kinases, and the self-renewal and metastasis of PANC-1 cells by suppressing cancer cell stemness. Furthermore, compound 4 induced ROS generation and subsequently activated autophagy, which was demonstrated by the formation of autophagic vacuoles and dynamic change of autophagic flux. The induced ROS accumulation resulted in AMPK activation and subsequently regulation of mTORC1 activity and ULK phosphorylation, indicating that 4 triggered autophagy through ROS/AMPK/mTORC1 pathway. These findings suggested that 4 might potentially be an autophagy inducer for the therapy of pancreatic cancer.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: