morphinans and Stomach-Neoplasms

Sinomenine (SIN) has been reported its antitumor effects on various types of human cancers, but there is no available information regarding the antitumor effects of SIN and cisplatin on gastric cancer. Here, we examined the antitumor effects of SIN combined with cisplatin on gastric cancer cells as well as the underlying biological mechanisms. CCK-8 assay and Calcusyn 2.0 software analysis, Hoechst 33258 staining and flow cytometry, transwell assay showed that SIN and cisplatin synergistically inhibited growth, induced apoptosis, and suppressed invasion than did either drug alone in gastric cancer cells. Interestingly, no change in the AKT level was found, whereas SIN and cisplatin led to a dramatic decrease in p-AKT level compared with either alone treatment. SIN and cisplatin further decreased the Bcl-2, procaspase-3, and β-catenin, but increased Bax, cleaved dcaspase 3, MMP9, and MMP2 in combined group than in either alone group. Immunofluorescence staining showed again a significant decrease in nucleus β-catenin was found in combined group. These data suggested that SIN sensitizes human gastric cancer cells to cisplatin through negative regulation of PI3K/AKT/Wnt signaling pathway. In conclusion, SIN and cisplatin exerted synergistic antitumor effects in gastric cancer cells and might constitute a promising therapeutic approach for gastric cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Synergism; Humans; Morphinans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Stomach Neoplasms; Wnt Signaling Pathway

Gastric carcinoma (GC) is a pernicious neoplasm with high morbidity and mortality. Sinomenine (SIN) has long been exploited to heal rheumatoid arthritis. Recently, SIN has been discovered to exert the antitumour functions in diverse cancers. However, the impacts of SIN on GC remain indistinct. We attempted to expose the antitumour effect of SIN on GC. MKN45 and SGC-7901 cells were administered with SIN for 24 hours, cell viability, proliferation, apoptosis, migration, invasion and the associated proteins in the above processes were examined via exploiting CCK-8, BrdU, flow cytometry, Transwell and Western blot. MiR-204 expression in GC tumour tissues, different GC cell lines and SIN-stimulated GC cells was investigated by executing RT-qPCR. The above cell biological processes were reassessed after transfection with miR-204 inhibitor. The latent mechanisms were probed by examining AMPK and Wnt/β-catenin pathways. We found that SIN memorably repressed cell proliferation, evoked apoptosis and affected CyclinD1, Bcl-2, Bax and cleaved-caspase-3 expression in MKN45 and SGC-7901 cells. Cell migration, invasion and expression of MMP-9 and Vimentin were all restrained by SIN stimulation. The increase of miR-204 was discovered in GC tissues and SIN-treated MKN45 and SGC-7901 cells. But suppression of miR-204 was observed in AGS, MKN28, MKN45 and SGC-7901 cells. Suppression of miR-204 overturned the inhibitory functions of SIN in MKN45 and SGC-7901 cells. Besides, SIN prohibited AMPK and Wnt/β-catenin pathways via enhancement of miR-204. In conclusion, these findings suggested that SIN exerted the antitumour activity in GC cells by hindering AMPK and Wnt/β-catenin pathways via enhancement of miR-204.

Topics: Adult; AMP-Activated Protein Kinases; Apoptosis; Carcinoma; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; Humans; Male; MicroRNAs; Middle Aged; Morphinans; Stomach; Stomach Neoplasms; Up-Regulation; Wnt Signaling Pathway