A novel ent-kaurane diterpenoid analog, DN3, selectively kills human gastric cancer cells via acting directly on mitochondria.

Abstract

Targeting mitochondria using proper pharmacological agents is considered an attractive strategy for cancer control and management. Herein, we report a newly synthetic triazole analog of Jaridonin, DN3, which exhibits more potent antitumor activity via acting directly on mitochondria. DN3 potently reduced viabilities of gastric cancer cell lines HGC-27 and MGC-803 through inducing apoptosis and cell cycle arrest. But, normal human gastric epithelial cell line GES-1 is more resistant to the growth inhibition by DN3 compared with gastric cancer cells. DN3 induced mitochondrial membrane potential (MMP) decrease and cytochrome c release in intact gastric cancer cell lines. Meanwhile, the DN3 treatment also caused the release of cytochrome c from mitochondria isolated from cancer cell lines in a mitochondrial permeability transition pore complex (PTPC) mediated manner, but not from mitochondria isolated from normal gastric epithelial cell. The induction of mitochondrial PTPC proteins voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) were also observed in DN3-treated cells. More interestingly, DN3 mediated MMP decrease, release of cytochrome c, the expression of VDAC and CypD and apoptosis were blocked by the pretreatment of VDAC1 inhibitor (4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid, DIDS) and CypD inhibitor (cyclosporine A, CsA). In a mouse xenograft model of human gastric cancer, the treatment of 5 mg/kg DN3 led to significant tumor regression without affecting body weight. In conclusion, our findings indicate that DN3 is a potential agent for the treatment of gastric cancer through acting directly on mitochondria, and would be useful for us to design more and better anti-cancer compounds.

• Authors: Yong-Cheng Ma, Ying-Li Zhu, Nan Su, Yu Ke, Xia-Xia Fan, Xiao-Jing Shi, Hong-Min Liu, Ai-Feng Wang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 848 Pg. 11-22 (Apr 05 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 30659827 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Diterpenes
• Diterpenes, Kaurane

Topics

• Animals
• Cell Line, Transformed
• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• Diterpenes (chemical synthesis, pharmacology, therapeutic use)
• Diterpenes, Kaurane (chemical synthesis, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (drug effects, metabolism, pathology)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Tumor Burden (drug effects, physiology)
• Xenograft Model Antitumor Assays (methods)