Troglitazone inhibits tumor growth in hepatocellular carcinomain vitroandin vivo

Abstract

Peroxisome proliferator-activated receptor ␥ (PPAR␥) has been implicated in the differentiation and growth inhibition of cancer cells. We examined the effects of PPAR␥ activation by troglitazone on hepatocellular carcinoma (HCC) cell growth, proliferation, and apoptosis in vitro and in vivo. We also studied relationships between PPAR␥ activation and cyclooxygenase-2 (COX-2) expression. Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone. Cell growth was determined via WST-1 assay, proliferation by cell cycle analysis and proliferating cell nuclear antigen ( O n a global scale, hepatocellular carcinoma (HCC) remains the third leading cause of cancer death due to both high incidence and poor survival. Although prevention of hepatitis B and C virus infections (primary prevention), cleaner water supplies, and more adequate antiviral treatment of advanced-stage hepatitis B and C (secondary prevention) can reduce the risk of HCC, there has been growing interest in the chemoprevention of cancer among high-risk individuals. At least some HCCs develop in a stepwise fashion from dysplastic lesions, through adenomatous proliferation to carcinoma in an analogous manner to colorectal carcinoma. The liver is therefore an attractive target for the identification and use of chemopreventive agents. In addition to DNA mutations, the biological processes relevant to hepatocarcinogenesis include disordered hepatocyte proliferation and operation of cell death pathways, particularly by apoptosis; these may be targets for chemopreventive agents.Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that mediate transcriptional regulation of genes involved in the oxidation, transport, and storage of lipids. 1 In addition to this pivotal role in lipid metabolism, PPARs influence such biological processes as inflammation,

Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARγ signaling pathway

“…Significantly increased COX-2 protein expression was observed in HCC tissues and cell lines [17,18] , which coincides with our results ( Figure 3A). To evaluate the significance of down-regulation of COX-2 expression in …”

CITED2 is a novel direct effector of peroxisome proliferator‐activated receptor γ in suppressing hepatocellular carcinoma cell growth

“…9,12,13 The precise mechanism and critical downstream effectors of PPARc in relation to its therapeutic efficacy in HCC, however, remains poorly understood. In this study, potential target genes under the control of PPARc in HCC were identified by microarray analysis of gene expression.…”

“…Hep3B cells (80% confluent) were exposed to 100 lM rosiglitazone for various times (3,8,12, or 24 hours). The PPARc/DNA binding activity in nuclear extract was measured using an enzyme-linked immunosorbent assay (ELISA)-based assay (Cayman Chemical, Ann Arbor, Mich).…”

Beyond peroxisome proliferator-activated receptor γ signaling: the multi-facets of the antitumor effect of thiazolidinediones

“…In the light of this cancer-specific effect, the potential use of these PPARg agonists as chemopreventive agents has received much attention (for a review see Badawi & Badr 2002, Kopelovich et al 2002, Smith & Kantoff 2002, Bull 2003, Koeffler 2003, Leibowitz & Kantoff 2003, Grommes et al 2004, Jiang et al 2004. Moreover, animal model studies have demonstrated the in vivo efficacy of troglitazone in colon, prostate, and liver cancers (Kubota et al 1998, Sarraf et al 1998, Yu et al 2006 and that of rosiglitazone in pituitary tumors (Henry et al 2000, Heaney et al 2002. Despite these advances, the mechanism underlying the antitumor effects of TZD remains unclear.…”