Isogarcinol inhibits nasopharyngeal carcinoma growth through mitochondria-mediated autophagic cell death

Li，Jing1; Shen，Xi2; Sun，Chunhui3; Hou，Yibo1; Hu，Ya4; Ma，Shaohua1; Huang，Laiqiang1; Ma，Lan1; Zhang，Yubo2; Dai，Xiaoyong1,2

2024-07-25

10.1016/j.phymed.2024.155745

Phytomedicine   影响因子和分区

0944-7113

1618-095X

Background and aims: Isogarcinol, a natural compound extracted from the fruits of Garcinia oblongifolia, has potential chemopreventive activity. This study aimed to elucidate the anti-tumor effects and mechanism of action of isogarcinol on nasopharyngeal carcinoma (NPC). Methods: Isogarcinol was isolated from Garcinia oblongifolia by using chromatographic separation. The anti-tumor effects of isogarcinol in NPC cells were tested by MTT assay, flow cytometry, wound healing assay, western blotting, transwell assay, colony formation assay, immunofluorescence, and transmission electron microscopy (TEM). The anti-tumor efficacy in vivo was evaluated in NPC cells xenograft models. Results: Functional studies revealed that isogarcinol inhibited the proliferation, colony formation, migration and invasion abilities of NPC cells in vitro. Isogarcinol caused mitochondrial damage to overproduce reactive oxygen species through reducing the mitochondrial membrane potential and ΔΨm. Isogarcinol also substantially inhibited NPC cells growth in a xenograft tumor model without any obvious toxicity when compared with paclitaxel (PTX). Mechanistic studies have illustrated that isogarcinol increased the Bax/Bcl-2 ratio, cleaved caspase-3, and cytoplasmic cytochrome C levels to induce mitochondrial apoptosis. The ROS overproduction by isogarcinol could suppress EMT pathway via decreasing the levels of p-Akt and Snail. Furthermore, isogarcinol promoted the conversion of LC3-Ⅰ to LC3-Ⅱ, but increased p62 level to block autophagic flux, resulting in the accumulation of damaged mitochondria to promote autophagic cell death in NPC cells. Conclusion: This study provides a new theoretical foundation for the anti-tumor application of Garcinia oblongifolia and confirms that isogarcinol could be developed as a candidate drug for NPC treatment with low toxicity.

Autophagic cell death Isogarcinol Mitochondrial apoptosis Nasopharyngeal carcinoma ROS

SCI

英语

其他

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85194890182

Scopus

1.Institute of Biopharmaceutical and Health Engineering,Shenzhen Key Laboratory of Gene and Antibody Therapy,State Key Laboratory of Chemical Oncogenomics,Tsinghua University Shenzhen International Graduate School,Shenzhen,University Town, Nanshan,518055,China
2.Guangdong Clinical Translational Center for Targeted Drug,Department of Pharmacology,School of Medicine,State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou,No. 601 Huangpu Avenue West, Tianhe District,510632,China
3.Research Center,Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research,The Seventh Affiliated Hospital of Sun Yat-Sen University,Shenzhen,No. 628 Zhenyuan Road, Xinhu Street, Guangming District,518107,China
4.Department of Stomatology,Shenzhen People's Hospital,the First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,No. 1017 East Gate North Road, Luohu District,518020,China

Li，Jing,Shen，Xi,Sun，Chunhui,et al. Isogarcinol inhibits nasopharyngeal carcinoma growth through mitochondria-mediated autophagic cell death[J]. Phytomedicine,2024,130.

Li，Jing.,Shen，Xi.,Sun，Chunhui.,Hou，Yibo.,Hu，Ya.,...&Dai，Xiaoyong.(2024).Isogarcinol inhibits nasopharyngeal carcinoma growth through mitochondria-mediated autophagic cell death.Phytomedicine,130.

Li，Jing,et al."Isogarcinol inhibits nasopharyngeal carcinoma growth through mitochondria-mediated autophagic cell death".Phytomedicine 130(2024).