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Troglitazone significantly reduced tumor growth in vivo, and caused tumor regression in liver cells
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Reported by Jules Levin
http://www.natap.org
from AASLD
Nov 11, 2005, San Francisco
Troglitazone is a member of a class of glitazones that are anti-diabetes drugs.
--(human HCC) cells were cultured in presence or absence of troglitazone;
--Tumor growth from subcutaneously implanted Huh7 cells in nude mice was monitored, and the effects of troglitazone determined.
--but troglitazone caused dose-dependent induction of PPARy
--These in vivo effects were also associated with suppression of cell proliferation and promotion of apoptosis
"PEROXISOMAL PROLIFERATOR-ACTIVATED RECEPTORGAMMA
ACTIVATION INHIBITS TUMOR PROGRESSION IN HEPATOCELLULAR CARCINOMA IN VITRO AND IN VIVO"
Jun Yu, Liang Qiao, University of Sydney, Sydney, Australia; Lars Zimmerman, Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Magdeburg, Germany; Matthias P. Ebert, Department of Pathology, Magdeburg, Germany; Geoffrey Farrell, University of Sydney, Sydney, Australia
Background and Aims: Peroxisome proliferator activated receptorgamma (PPARy) receptors have been implicated in differentiation and growth inhibition of cancer cells. We therefore examined expression of PPARy in resected human hepatocellular carcinoma (HCC) and surrounding liver, as well as in HCC cell lines. We then studied effects of ligand-mediated PPARy activation on
growth, proliferation and death of HCC cells in vitro and in vivo, and clarified relationships between PPAR activation and cyclooxygenase 2 (COX-2) expression.
Methods: PPARy and COX-2 mRNA and protein levels were determined by real time PCR and western immunoblotting (WB), respectively. Huh7 and Hep3B
(human HCC) cells were cultured in presence or absence of troglitazone;
cell growth was by WST-1 assay, proliferation by cell cycle analysis and PCNA WB, apoptosis by flow cytometry and TUNEL. Tumor growth from subcutaneously implanted Huh7 cells in nude mice was monitored, and the effects of troglitazone determined.
Results:
PPARy expression was less in HCC tissue than in histologically normal surrounding liver. In Hep3B and Huh7 cells, basal PPARy expression was relatively low, but troglitazone caused dose-dependent induction of PPARy. Such induction suppressed HCC cell viability in a dose-dependent fashion. Further, cell cycle analysis revealed a decreased proportion of cells in S-phase, with arrest at G0/G1, and there was concomitant downregulation of PCNA. Conversely, PPARy stimulation by troglitazone increased TUNEL immunostaining, consistent with decreased cell proliferation and induction of apoptosis. Ligand-mediated PPARy activation also suppressed COX-2 expression in liver cancer cells. In nude mice inoculated with Huh7 cells subcutaneously, troglitazone significantly reduced tumor growth in vivo, and caused tumor regression. These in vivo effects were also associated with suppression of cell proliferation and promotion of apoptosis.
Conclusions: PPARy can regulate cell survival and growth in at least some HCC cells, and therefore represents a novel molecular target for chemopreventive therapy or to inhibit growth of established liver cancer.
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