2-Pyrazine-PPD, a novel dammarane derivative, showed anticancer activity by reactive oxygen species-mediate apoptosis and endoplasmic reticulum stress in gastric cancer cells

• Published in: European journal of pharmacology 2020-08, Vol.881, p.173211-173211, Article 173211
• Main Authors: De Wang, Xu, Li, Tao, Li, Yan, Yuan, Wei Hui, Zhao, Yu Qing
• Format: Article
• Language: English
• Subjects: 2-Pyrazine-PPD; 25-OH-PPD; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Ginsenosides - pharmacology; Humans; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Oxidative Stress - drug effects; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173211

20 (R)-Dammarane-3β, 12β, 20, 25-tetrol (25-OH-PPD), a ginsenoside, was derived from Panax ginseng (C. A. Meyer) and inhibited growth of several cancer cell lines. To improve the anti-cancer activity, we introduced the pyrazine ring to 25-OH-PPD and obtained the compound 20(R)-[2,3-β]-Pyrazine-dammarane-12β,20,25-triol (2-Pyrazine-PPD). we evaluated the anti-cancer activity of 2-Pyrazine-PPD and investigated the main anti-cancer mechanisms of 2-Pyrazine-PPD in gastric cancer cells. We found that 2-Pyrazine-PPD remarkably suppressed the proliferation of gastric cancer cells in a concentration-dependent, and showed little toxicity to the normal cell (human gastric epithelial cell line-GES-1). Further study indicated that 2-Pyrazine-PPD induced apoptosis by mitochondria pathway in BGC-803 cancer cells, and activated unfolded protein response and the protein kinase RNA-activated (PKR)-like ER kinase (PERK)/Eukaryotic translation initiation factor-2α (eIF-2α)/Activating transcription factor 4 (ATF4) axis, the expression level of the protein C/EBP homologous protein (CHOP), the marker of endoplasmic reticulum stress, and the apoptosis inducing by 2-Pyrazine-PPD can partly be inhibited by siRNA-mediated knockdown of CHOP. Moreover, the production of reactive oxygen species was remarkably up-regulated in BGC-803 cancer cells treated with 2-Pyrazine-PPD. N-acetylcysteine (NAC, a reactive oxygen species scavenger) can attenuate 2-Pyrazine-PPD-induced apoptosis and endoplasmic reticulum stress. Taken together, we suggested that 2-Pyrazine-PPD exhibited remarkable anti-cancer activity by reactive oxygen species-mediate cell apoptosis and endoplasmic reticulum stress in gastric cancer cells. Our results uncovered the mechanism of 2-Pyrazine-PPD as a promising anti-tumor candidate for gastric cancer therapy. [Display omitted]