Download PDF
Planta Med 2008; 74(8): 834-839
DOI: 10.1055/s-2008-1074555
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Isoliquiritigenin Inhibits Cell Proliferation by a Heme Oxygenase-Dependent Pathway in Rat Hepatic Stellate Cells

Sun Wook Woo1 , Sung Hee Lee2 , Geonil Ko2 , Youn-Chul Kim2 , Dong Hwan Sohn2
  • 1National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, South Korea
  • 2Department of Pharmacy, Medicinal Resources Research Center, Wonkwang University, Iksan, Jeonbuk, South Korea
Further Information

Publication History

Received: February 12, 2008 Revised: April 17, 2008

Accepted: May 4, 2008

Publication Date:
18 June 2008 (online)

Also available at
    Permissions and Reprints

Abstract

We evaluated whether the antiproliferative effects of isoliquiritigenin (ISL) on rat hepatic stellate cells (HSCs) are related to the induction of heme oxygenase 1 (HO-1) expression. ISL significantly inhibited serum- or growth factor-induced HSC proliferation. The inhibition of platelet-derived growth factor (PDGF)-induced proliferation by ISL was associated with the mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt-p70S6K pathways. ISL induced the expression of HO-1 in HSCs. Using the chemical inhibitor tin protoporphyrin, we also found that the inhibitory action of ISL on PDGF-induced proliferation is mediated by HO-1. These data suggest that HO-1 expression is responsible for the antiproliferative effect of ISL on HSCs.

Key words

isoliquiritigenin - Dalbergia odorifera T. Chen - Leguminosae - hepatic stellate cell - heme oxygenase 1 - mitogen-activated protein kinase

References

  • 1 Maines M D. The heme oxygenase system: a regulator of second messenger gases.  Annu Rev Pharmacol Toxicol. 1997;  37 517-54
    CrossrefPubMedSearch in Google Scholar
  • 2 Maines M D, Trakshel G M, Kutty R K. Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible.  J Biol Chem. 1986;  261 411-9
    PubMedSearch in Google Scholar
  • 3 Choi B M, Kim Y M, Jeong Y R, Pae H O, Song C E, Park J E. et al . Induction of heme oxygenase-1 is involved in anti-proliferative effects of paclitaxel on rat vascular smooth muscle cells.  Biochem Biophys Res Commun. 2004;  321 132-7
    CrossrefPubMedSearch in Google Scholar
  • 4 Li L, Julien B, Grenard P, Teixeira-Clerc F, Mallat A, Lotersztajn S. Molecular mechanisms regulating the antifibrogenic protein heme-oxygenase-1 in human hepatic myofibroblasts.  J Hepatol. 2004;  41 407-13
    CrossrefPubMedSearch in Google Scholar
  • 5 Calliste C A, Le Bail J C, Trouillas P, Pouget C, Habrioux G, Chulia A J. et al . Chalcones: structural requirements for antioxidant, estrogenic and antiproliferative activities.  Anticancer Res. 2001;  21 3949-56
    PubMedSearch in Google Scholar
  • 6 Lee S H, Seo G S, Kim H S, Woo S W, Ko G, Sohn D H. 2′,4′,6′-Tris(methoxymethoxy) chalcone attenuates hepatic stellate cell proliferation by a heme oxygenase-dependent pathway.  Biochem Pharmacol. 2006;  72 1322-33
    CrossrefPubMedSearch in Google Scholar
  • 7 Foresti R, Hoque M, Monti D, Green C J, Motterlini R. Differential activation of heme oxygenase-1 by chalcones and rosolic acid in endothelial cells.  J Pharmacol Exp Ther. 2005;  312 686-93
    PubMedSearch in Google Scholar
  • 8 Woo S W, Lee S H, Kang H C, Park E J, Zhao Y Z, Kim Y C. et al . Butein suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture.  J Pharm Pharmacol. 2003;  55 347-52
    CrossrefPubMedSearch in Google Scholar
  • 9 Namikoshi M, Nakata H, Nuno M, Ozawa T, Saitoh T. Homoisoflavonoids and related compounds. III. Phenolic constituents of Caesalpinia japonica SIEB. et ZUCC.  Chem Pharm Bull. 1987;  35 3568-75
    CrossrefPubMedSearch in Google Scholar
  • 10 Johnson M D, Woodard A, Kim P, Frexes-Steed M. Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells.  J Neurosurg. 2001;  94 293-300
    CrossrefPubMedSearch in Google Scholar
  • 11 Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells.  Semin Liver Dis. 2001;  21 397-416
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Marra F, Gentilini A, Pinzani M, Choudhury G G, Parola M, Herbst H. et al . Phosphatidylinositol 3-kinase is required for platelet-derived growth factor′s actions on hepatic stellate cells.  Gastroenterology. 1997;  112 1297-306
    CrossrefPubMedSearch in Google Scholar
  • 13 Berven L A, Willard F S, Crouch M F. Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration.  Exp Cell Res. 2004;  296 183-95
    CrossrefPubMedSearch in Google Scholar
  • 14 Ui M, Okada T, Hazeki K, Hazeki O. Wortmannin as a unique probe for an intracellular signalling protein, phosphoinositide 3-kinase.  Trends Biochem Sci. 1995;  20 303-7
    CrossrefPubMedSearch in Google Scholar
  • 15 Kyriakis J M, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation.  Physiol Rev. 2001;  81 807-69
    CrossrefPubMedSearch in Google Scholar
  • 16 Marra F, Arrighi M C, Fazi M, Caligiuri A, Pinzani M, Romanelli R G. et al . Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor′s actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat.  Hepatology. 1999;  30 951-8
    CrossrefPubMedSearch in Google Scholar
  • 17 Schnabl B, Bradham C A, Bennett B L, Manning A M, Stefanovic B, Brenner D A. et al . TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells.  Hepatology. 2001;  34 953-63
    CrossrefPubMedSearch in Google Scholar
  • 18 Hsu Y L, Kuo P L, Lin L T, Lin C C. Isoliquiritigenin inhibits cell proliferation and induces apoptosis in human hepatoma cells.  Planta Med. 2005;  71 130-4
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Ryter S W, Otterbein L E, Morse D, Choi A M. Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance.  Mol Cell Biochem. 2002;  234 – 235 249-63
    CrossrefPubMedSearch in Google Scholar
  • 20 Marra F, Pinzani M, DeFranco R, Laffi G, Gentilini P. Involvement of phosphatidylinositol 3-kinase in the activation of extracellular signal-regulated kinase by PDGF in hepatic stellate cells.  FEBS Lett. 1995;  376 141-5
    CrossrefPubMedSearch in Google Scholar
  • 21 Tsui T Y, Lau C K, Ma J, Wu X, Wang Y Q, Farkas S. et al . rAAV-mediated stable expression of heme oxygenase-1 in stellate cells: a new approach to attenuate liver fibrosis in rats.  Hepatology. 2005;  42 335-42
    CrossrefPubMedSearch in Google Scholar
  • 22 Li L, Grenard P, Nhieu J T, Julien B, Mallat A, Habib A. et al . Heme oxygenase-1 is an antifibrogenic protein in human hepatic myofibroblasts.  Gastroenterology. 2003;  125 460-9
    CrossrefPubMedSearch in Google Scholar
  • 23 Immenschuh S, Ramadori G. Gene regulation of heme oxygenase-1 as a therapeutic target.  Biochem Pharmacol. 2000;  60 1121-8
    CrossrefPubMedSearch in Google Scholar
  • 24 Zhang X, Bedard E L, Potter , Zhong R, Alam J, Choi A M. et al . Mitogen-activated protein kinases regulate HO-1 gene transcription after ischemia-reperfusion lung injury.  Am J Physiol Lung Cell Mol Physiol. 2002;  283 L815-29
    CrossrefPubMedSearch in Google Scholar

Dong Hwan Sohn

Department of Pharmacy

Wonkwang University

Iksan

Jeonbuk 570–749

South Korea

Phone: +82-63-850-6822

Fax: +82-63-854-6038

Email: dhsohn@wonkwang.ac.kr