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Oncol Rep. 2013 Feb;29(2):751-62. doi: 10.3892/or.2012.2166. Epub 2012 Dec 5.

Smh-3 induces G(2)/M arrest and apoptosis through calcium‑mediated endoplasmic reticulum stress and mitochondrial signaling in human hepatocellular carcinoma Hep3B cells.

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Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung 404, Taiwan, ROC.


In the present study, we investigated the antitumor effects of Smh-3 on the viability, cell cycle and apoptotic cell death in human hepatocellular carcinoma Hep3B cells in vitro. We also investigated the molecular mechanisms involved in the effects of Smh-3 on human hepatoma Hep3B cells, including the effects on protein and mRNA levels which were determined by western blotting and DNA microarray methods, respectively. The results demonstrated that Smh-3 induced growth inhibition, cell morphological changes and induction of G(2)/M arrest and apoptosis in Hep3B cells. DNA microarray assay identified numerous differentially expressed genes related to angiogenesis, autophagy, calcium-mediated ER stress signaling, cell adhesion, cell cycle and mitosis, cell migration, cytoskeleton organization, DNA damage and repair, mitochondrial-mediated apoptosis and cell signaling pathways. Furthermore, Smh-3 inhibited CDK1 activity, mitochondrial membrane potential (ΔΨm) and increased the cytosolic Ca(2+) release and caspase-4, caspase-9 and caspase-3 activities in Hep3B cells. Western blot analysis demonstrated that Smh-3 increased the protein levels of caspase-4 and GADD153 that may lead to ER stress and consequently apoptosis in Hep3B cells. Taken together, Smh-3 acts against human hepatocellular carcinoma Hep3B cells in vitro through G(2)/M phase arrest and induction of calcium-mediated ER stress and mitochondrial-dependent apoptotic signaling pathways.

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