1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPARγ-dependent and PPARγ-independent pathways

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing p-trifluoromethyl, t-butyl, and phenyl [1,1-bis(3'indolyl)-1-(p-phenyl)methane (DIM-C-pPhC(6)H(5))] substituents induce peroxisome proliferator-activated receptor gamma (PPAR gamma)-mediated transactivation in SW480 colon cancer cells. These PPAR gamma-active compounds also inhibit cell proliferation and modulate some cell cycle proteins. At concentrations from 2.5 to 7.5 mu mol/L, the PPAR gamma agonists induce caveolin-1 and phosphorylation of Akt and cotreatment with the PPAR gamma antagonist GW9662 inhibited the induction response. In contrast, higher concentrations (10 mu mol/L) of 1,1-bis(3'-indolyl)-1-(p-substituted pheny0methanes containing 1,1-bis(3'indolyi)-1-(p -trifluoromethyl) methane and DIM-C-pPhC6H5 induce apoptosis, which is PPAR gamma independent. This was accompanied by loss of caveolin-1 induction but induction of proapoptotic nonsteroidal anti-inflammatory drug activated gene-1. In athymic nude mice bearing SW480 cell xenografts, DIM-C-pPhC6H5 inhibits tumor growth at doses of 20 and 40 mg/kg/d and immunohistochemical staining of the tumors showed induction of apoptosis and nonsteroidal anti-inflammatory drug activated gene-1 expression. Thus, the indole-derived PPAR gamma-active compounds induce both receptor-dependent and receptor-independent responses in SW480 cells, which are separable over a narrow range of concentrations. This dual mechanism of action enhances their anti proliferative and anticancer activities.