Mechanisms Mediating the Effects ofγ-Tocotrienol When Used in Combination with PPARγAgonists or Antagonists on MCF-7 and MDA-MB-231 Breast Cancer Cells

Abstract

γ-Tocotrienol is a natural vitamin E that displays potent anticancer activity, and previous studies suggest that these effects involve alterations in PPARγ activity. Treatment with 0.5–6 μM γ-tocotrienol, 0.4–50 μM PPARγ agonists (rosiglitazone or troglitazone), or 0.4–25 μM PPARγ antagonists (GW9662 or T0070907) alone resulted in a dose-responsive inhibition of MCF-7 and MDA-MB-231 breast cancer proliferation. However, combined treatment of 1–4 μM γ-tocotrienol with PPARγ agonists reversed the growth inhibitory effects of γ-tocotrienol, whereas combined treatment of 1–4 μM γ-tocotrienol with PPARγ antagonists synergistically inhibited MCF-7 and MDA-MB-231 cell growth. Combined treatment of γ-tocotrienol and PPARγ agonists caused an increase in transcription activity of PPARγ along with increased expression of PPARγ and RXR, and decrease in PPARγ coactivators, CBP p/300, CBP C-20, and SRC-1, in both breast cancer cell lines. In contrast, combined treatment of γ-tocotrienol with PPARγ antagonists resulted in a decrease in transcription activity of PPARγ, along with decreased expression of PPARγ and RXR, increase in PPARγ coactivators, and corresponding decrease in PI3K/Akt mitogenic signaling in these cells. These findings suggest that elevations in PPARγ are correlated with increased breast cancer growth and survival, and treatment that decreases PPARγ expression may provide benefit in the treatment of breast cancer.

Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology

“…autophagy induction and ER stress-mediated apoptosis Tiwari et al, 2015). Furthermore, tocotrienols have been successfully used as anticancer agents in combination therapies (Abdul Kani et al, 2013;Malaviya and Sylvester, 2013;Rezaei et al, 2014;Sylvester et al, 2011;Tiwari et al, 2015;Tuerdi et al, 2013;Yusof et al, 2015), as agents against cardiovascular diseases (Prasad, 2011) and as radioprotectors in patients undergoing radiotherapy (Kulkarni et al, 2010;Singh et al, 2013).…”

Influence of 17β-Estradiol on 15-Deoxy-Δ12,14Prostaglandin J2-Induced Apoptosis in MCF-7 and MDA-MB-231 Cells

“…In fact, direct antiproliferative effect of GW9662 has previously been reported in MCF-7, MDA-MB-231 and MDA-MB-468 cells (Sergeant et al, 2004;Malaviya and Sylvester, 2013). A higher concentration of the antagonist (20 μM) was also reported to cause extensive cell death .…”

Screening of Alternative Drugs to the Tumor Suppressor miR-375 in Esophageal Squamous Cell Carcinoma Using the Connectivity Map

“…Studies have demonstrated the anticancer effects of rosiglitazone and the activation of peroxisome proliferator-activated receptor-γ agonists in several cancers, including hepatocellular carcinoma, breast cancer and colon cancer among others [26,27,28]. Among the 8 identified drugs, there are few articles showing that fosfosal, stachydrine, nizatidine and benzocaine are associated with cancer.…”