In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 7, No. 7 ( 2008-07-01), p. 2203-2211
Abstract:
We found previously that X-linked inhibitor of apoptosis protein (XIAP), a potent endogenous inhibitor of apoptosis, is overexpressed in colon cancer. Ligand-induced activation of peroxisome proliferator-activated receptor γ (PPARγ) has been shown to exert proapoptotic and antiproliferative effects in many cancer cell types. However, neither XIAP down-regulation alone nor monotherapy using PPARγ ligands is potent enough to control colon cancer. We explored whether XIAP inhibition and PPARγ activation offer a synergistic anticancer effect in colon cancer. HCT116-XIAP+/+ and HCT116-XIAP-/- cells were treated with troglitazone or 15-deoxy-Δ12,14-prostaglandin J2 (15-PGJ2). Cell growth and apoptosis were measured. Nude mice were s.c. inoculated with HCT116 cells with or without oral troglitazone. Tumor growth, angiogenesis, and apoptosis were measured. Troglitazone- and 15-PGJ2-induced growth inhibition and apoptosis were more prominent in HCT116-XIAP-/- cells. Troglitazone- and 15-PGJ2-induced apoptosis correlated with enhanced cleavage of caspases and poly(ADP-ribose) polymerase, which were more profound in HCT116-XIAP-/- cells. Pretreatment of cells with XIAP inhibitor 1396-12 also sensitized HCT116-XIAP+/+ cells to PPARγ ligand-induced apoptosis. Troglitazone significantly retarded the growth of xenograft tumors, more significantly so in HCT116-XIAP-/- cell-derived tumors. Reduction of tumor size was associated with reduced expression of Ki-67, vascular endothelial growth factor, and CD31 as well as increased apoptosis. Loss of XIAP significantly sensitized colorectal cancer cells to PPARγ ligand-induced apoptosis and inhibition of cell proliferation. Thus, simultaneous inhibition of XIAP and activation of PPARγ may have a synergistic antitumor effect against colon cancer. [Mol Cancer Ther 2008;7(7):2203–11]
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.MCT-08-0326
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2008
detail.hit.zdb_id:
2062135-8
SSG:
12
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