Synergistic antiproliferative effects of combined γ-tocotrienol and PPAR γ antagonist treatment are mediated through PPAR γ-independent mechanisms in breast cancer cells

Previous findings showed that the anticancer effects of combined γ-tocotrienol and peroxisome proliferator activated receptor γ (pparγ) antagonist treatment caused a large reduction in pparγ expression. however,other studies suggest that the antiproliferative effects of γ-tocotrienol and/or pparγ antagonists are mediated,at least in part,through pparγ-independent mechanism(s). studies were conducted to characterize the role of pparγ in mediating the effects of combined treatment of γ-tocotrienol with pparγ agonists or antagonists on the growth of pparγ negative +sa mammary cells and pparγ-positive and pparγ-silenced mcf-7 and mda-mb-231 breast cancer cells. combined treatment of γ-tocotrienol with pparγ antagonist decreased,while combined treatment of γ-tocotrienol with pparγ agonist increased,growth of all cancer cells. however,treatment with high doses of 15d-pgj 2,an endogenous natural ligand for pparγ,had no effect on cancer cell growth. western blot and qrt-pcr studies showed that the growth inhibitory effects of combined γ-tocotrienol and pparγ antagonist treatment decreased cyclooxygenase (cox-2),prostaglandin synthase (pgds),and prostaglandin d2 (pgd2) synthesis. in conclusion,the anticancer effects of combined γ-tocotrienol and pparγ antagonists treatment in pparγ negative/silenced breast cancer cells are mediated through pparγ-independent mechanisms that are associated with a downregulation in cox-2,pgds,and pgd2 synthesis. © 2014 abhita malaviya and paul w. sylvester.