HS-4,a highly potent inhibitor of cell proliferation of human cancer cell

Objective:To investigate the antitumor activity of the compound HS-4 and the action mechanism.Methods:MTT method was used to test in vitro antitumor activity of the compound HS-4.Orthotopic xenotransplantation tumor model of liver cancer was established in nude mice,and.in vivo antitumor activity of compound HS-4 was tested with a small animal in-vivo imaging system.Sequencing of small RNA library and RNA library was performed in HS-4 treated tumor cell group and control group to investigate the anti-cancer mechanism of HS-4 at level of functional genomics,using high-throughput sequencing technology.Results:HS-4 was found to have relatively high in-vitro antitumor activity against liver cancer cells,gastric cancer cells,renal cancer cells,lung cancer cells,breast cancer cells and colon cancer cells.The IC_(50) values against SMMC-7721 and Bel-7402 of liver cancer cells were 0.14 and 0.13 nmol/L respectively,while the IC_(50) values against MGC-803 and SGC-7901 of gastric cancer cells were 0.19 and 0.21 nmol/L,respectively.It was demonstrated that HS- 4 possessed a betler therapeutic effect in liver cancer.Conclusions:A new reliable orthotopicxenotransplantation tumor model of liver cancer in nude mice is established.The new compounds HS-4 was found to possess relatively high in vivo and in vitro antitumor activity against liver cancer cells.

G9a-targeted chaetocin induces pyroptosis of gastric cancer cells

Objective:To evaluate the effect of chaetocin on pyroptosis of gastric cancer cells and its underlying mechanisms.Methods:The proliferation of gastric cancer cells was detected by trypan blue staining.Flow cytometry and Hoechst/propidium iodide double staining were used to detect apoptosis and pyroptosis.Cellular ultrastructure was observed by transmission electron microscopy.The levels of p-mixed lineage kinase domain-like(MLKL),gasdermin-D(GSDMD),gasdermin E(GSDME),N-GSDMD,and N-GSDME proteins were detected by Western blotting.In addition,lactate dehydrogenase(LDH)release assay was used to verify pyroptosis induced by chaetocin,and caspase 3 inhibition test and siRNA interference test were conducted to investigate pyroptosis mechanisms.Results:Chaetocin at concentrations of 200 nmol/L to 600 nmol/L inhibited the proliferation of AGS,HGC27,MKN28,and SGC7901gastric cancer cells in a dose-dependent and time-dependent manner by inducing apoptosis and pyroptosis.Significant ultrastructure changes,such as chromatin condensation,vacuolization,disrupted mitochondrial cristae,and increased nuclear occupancy,were observed after treatment with chaetocin in SGC7901 cells.Chaetocin at a concentration of 400 nmol/L significantly increased the number of pyroptotic cells,LDH release,and the ratio of N-GSDME/GSDME(P<0.01),which were reversed by Z-DEVD-FMK.In addition,chaetocin did not affect the expression of GSDMD.G9a silencing abolished the effect of chaetocin on the expression levels of GSDME and N-GSDME and LDH release(P>0.05).Conclusions:In addition to inducing apoptosis,chaetocin inhibits gastric cancer cells by inducing pyroptosis via the caspase 3/GSDME pathway.G9a was the target of chaetocin to induce pyroptosis of gastric cancer cells.