1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPARgamma-dependent and PPARgamma-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 (PPARgamma)-mediated transactivation in SW480 colon cancer cells. These PPARgamma-active compounds also inhibit cell proliferation and modulate some cell cycle proteins. At concentrations from 2.5 to 7.5 micromol/L, the PPARgamma agonists induce caveolin-1 and phosphorylation of Akt and cotreatment with the PPARgamma antagonist GW9662 inhibited the induction response. In contrast, higher concentrations (10 micromol/L) of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing 1,1-bis(3'-indolyl)-1-(p-trifluoromethyl)methane and DIM-C-pPhC(6)H(5) induce apoptosis, which is PPARgamma 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-pPhC(6)H(5) 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 PPARgamma-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 antiproliferative and anticancer activities.
Chintharlapalli
Sudhakar
S
Department of Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Veterinary Research Building 410, College Station, TX 77843-4466, USA.
Papineni
Sabitha
S
Safe
Stephen
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051242:Caveolin 1 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
C505817:1,1-bis(3'-indolyl)-1-(4-biphenyl)methane; C505816:1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane; C492909:1,1-bis(3'-indolyl)-1-(4-trifluoromethylphenyl)methane; D000970:Antineoplastic Agents; D051242:Caveolin 1; D007211:Indoles; D047495:PPAR gamma; D011065:Poly(ADP-ribose) Polymerases