Differential effects of resveratrol and novel resveratrol derivative, HS-1793, on endoplasmic reticulum stress-mediated apoptosis and Akt inactivation.

Abstract	Since resveratrol (3,4',5 tri-hydroxystilbene), which has been shown to inhibit multistage carcinogenesis, is not a potent cytotoxic compound, several studies were undertaken to obtain synthetic analogues of resveratrol with potent activity. We previously reported that a resveratrol derivative HS-1793 exhibits stronger antitumor effects than resveratrol in several cancer cell types. The present study was undertaken to reveal precise mechanism by which HS-1793 induces cell death. The induction of CCAAT/enhancer-binding protein-homologous protein (CHOP) and glucose-regulated protein (GRP)-78, and ER stress-specific XBP1 splicing were found in HT29 human colon carcinoma cells treated with resveratrol. Conversely, these manifestations were not observed in HT29 cells treated with HS-1793. Inhibition of caspase-4 activity by z-LEVD-fmk significantly reduced the induction of apoptosis by resveratrol but not by HS-1793. These findings suggest that HS-1793, contrary to resveratrol, does not induce ER stress-mediated apoptosis. Importantly, we observed that HS-1793 but not resveratrol decreased phosphorylated Akt level. We also demonstrated that HS-1793, compared to resveratrol, exerted more effective apoptosis inducing activity in Akt-activated cells. Taken together, the stronger antitumor activity of HS-1793 originates, at least in part, from its ability for Akt inactivation.
Authors	Hee Jung Um, Jae Hoon Bae, Jong-Wook Park, Hongsuk Suh, Na Young Jeong, Young Hyun Yoo, Taeg Kyu Kwon
Journal	International journal of oncology (Int J Oncol) Vol. 36 Issue 4 Pg. 1007-13 (Apr 2010) ISSN: 1791-2423 [Electronic] Greece
PMID	20198347 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	4-(6-hydroxy-2-naphthyl)-1,3-benzenediol Antineoplastic Agents, Phytogenic Caspase Inhibitors Cysteine Proteinase Inhibitors DDIT3 protein, human DNA-Binding Proteins Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins Naphthols RNA, Messenger Regulatory Factor X Transcription Factors Resorcinols Stilbenes Transcription Factors X-Box Binding Protein 1 XBP1 protein, human Transcription Factor CHOP Proto-Oncogene Proteins c-akt CASP4 protein, human Caspases, Initiator Resveratrol Calcium
Topics	Antineoplastic Agents, Phytogenic (pharmacology) Apoptosis (drug effects) Calcium (metabolism) Caspase Inhibitors Caspases, Initiator (metabolism) Cell Proliferation (drug effects) Cysteine Proteinase Inhibitors (pharmacology) DNA-Binding Proteins (genetics) Dose-Response Relationship, Drug Endoplasmic Reticulum (drug effects, enzymology) Endoplasmic Reticulum Chaperone BiP Enzyme Activation HT29 Cells Heat-Shock Proteins (metabolism) Humans Naphthols (pharmacology) Phosphorylation Proto-Oncogene Proteins c-akt (metabolism) RNA Splicing RNA, Messenger (metabolism) Regulatory Factor X Transcription Factors Resorcinols (pharmacology) Resveratrol Signal Transduction (drug effects) Stilbenes (pharmacology) Stress, Physiological (drug effects) Transcription Factor CHOP (metabolism) Transcription Factors (genetics) X-Box Binding Protein 1

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