論文

査読有り
2004年10月

Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells

CLINICAL CANCER RESEARCH
  • M Shimizu
  • ,
  • M Suzui
  • ,
  • A Deguchi
  • ,
  • JTE Lim
  • ,
  • DH Xiao
  • ,
  • JH Hayes
  • ,
  • KP Papadopous
  • ,
  • IB Weinstein

10
19
開始ページ
6710
終了ページ
6721
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/1078-0432.CCR-04-0659
出版者・発行元
AMER ASSOC CANCER RESEARCH

Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of post-surgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 mumol/L acyclic retinoid and 0.01 mumol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-x(L), and activation of caspase-3, -8, and -9. OSI-461 enhanced the G(0)-G(1) arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21(CIPI) protein and mRNA, and stimulated p21(CIPI) promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIPI) and retinoic acid receptor beta expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.

Web of Science ® 被引用回数 : 26

リンク情報
DOI
https://doi.org/10.1158/1078-0432.CCR-04-0659
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/15475462
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000224521300037&DestApp=WOS_CPL

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