Abstract
A new series of etherification chalcone derivatives were designed and synthesized through Willimison etherification and Claisen-Schmidt condensation. Among them, compound 2-c which was given chemical name of S17, has been successfully screened out as the most potent one on gastric cancer cell line(MGC803) through the investigation for their effects against the growth of five cancer cell lines (EC109, HepG2, MCF7, MGC803, SKNSH). S17 exhibited strong anti-proliferative activity on other two gastric cancer cells (HGC27 and SGC7901), but less cytotoxicity to non-malignant gastric epithelial cells GES1. S17 potently killed gastric cancer cells with causing modulation of Bcl-2 family proteins and activation of caspase 9/3 cascade. S17 also up-regulated DR5 expression and DR5 knockdown partially reversed S17-induced apoptosis, caspase activation and MMP decrease. S17 robustly induced generation of ROS with Keap/Nrf2 pathway activated and the application of ROS scavenger N-acetyl cysteine (NAC) completely blocked these effects by S17 in MGC803 cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.
Highlights
Title A novel chalcone derivative S17 induces apoptosis through Reactive oxygen species (ROS) dependent DR5 upregulation in gastric cancer cells
In comparison with the control cells, S17 treatment of MGC803 cells led to a significant increase in the protein levels of BimEL, Bax, t-Bid and a reduction in the protein levels of XIAP in a time-dependent manner, whereas the levels of anti-apoptotic Bcl-2, Bcl-xL and death receptor family protein DR4 were not changed. These results revealed that the mitochondrial pathway plays an important role in S17 induced apoptosis in gastric cancer cells
Carcinogenesis is a complex process which consists of a series proliferative signaling, including evasion of growth suppression, damaged extracellular matrix (ECM) components, resistance to cell death, uncontrolled proliferation as well as increasing invasion and metastasis of cancer cells[26, 27]
Summary
Title A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 upregulation in gastric cancer cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer. A chalcone panduratin A isolated from Kaempferia pandurata induce apoptosis and cell cycle arrest in androgen-independent human prostate cancer cells PC3 and DU1459 These observations suggested that naturally-occurring chalcone can be further optimized through synthesis of their derivatives as new anti-cancer agents to effectively treat certain cancers. Reactive oxygen species (ROS), a cellular metabolite which regulates multiple cancer-related signalling pathways appears to be an important regulatory signal of cell apoptosis[11] A series of etherified chalcone derivatives were rationally designed and their antitumor activities evaluated
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