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)

    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
    CrossrefPubMedGoogle 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
    PubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    PubMedGoogle 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
    CrossrefPubMedGoogle 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
    PubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle Scholar
  • 11 Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells.  Semin Liver Dis. 2001;  21 397-416
    Article in Thieme ConnectPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    Article in Thieme ConnectPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle Scholar
  • 23 Immenschuh S, Ramadori G. Gene regulation of heme oxygenase-1 as a therapeutic target.  Biochem Pharmacol. 2000;  60 1121-8
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle 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

      >