1,1-Bis(3′-indolyl)-1-( p -substitutedphenyl)methanes Induce Peroxisome Proliferator-Activated Receptor γ-Mediated Growth Inhibition, Transactivation, and Differentiation Markers in Colon Cancer Cells

Abstract

1,1-Bis(3′indolyl)-1–(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF₃), p-t-butyl (DIM-C-pPhtBu), and p-phenyl (DIM-C-pPhC₆H₅) groups induce peroxisome proliferator-activated receptor γ (PPARγ)-mediated transactivation in HT-29, HCT-15, RKO, and SW480 colon cancer cell lines. Rosiglitazone also induces transactivation in these cell lines and inhibited growth of HT-29 cells, which express wild-type PPARγ but not HCT-15 cells, which express mutant (K422Q) PPARγ. In contrast, DIM-C-pPhCF₃, DIM-C-pPhtBu, and DIM-C-pPhC₆H₅ inhibited growth of both HT-29 and HCT-15 cells with IC₅₀ values ranging from 1 to 10 μmol/L. Rosiglitazone and diindolylmethane (DIM) analogues did not affect expression of cyclin D1, p21, or p27 protein levels or apoptosis in HCT-15 or HT-29 cells but induced keratin 18 in both cell lines. However, rosiglitazone induced caveolins 1 and 2 in HT-29 but not HCT-15 cells, whereas these differentiation markers were induced by DIM-C-pPhCF₃ and DIM-C-pPhC₆H₅ in both cell lines. Because overexpression of caveolin 1 is known to suppress colon cancer cell and tumor growth, the growth inhibitory effects of rosiglitazone and the DIM compounds are associated with PPARγ-dependent induction of caveolins.