Journal of Pharmacy and Nutrition Sciences, 2014, 4, 43-56 43 ISSN: 2223-3806 / E-ISSN: 1927-5951/14 © 2014 Lifescience Global Anticancer Effects of Combined  -Tocotrienol and PPAR Antagonist Treatment are Associated with a Suppression in Adipogenic Factor Expression Abhita Malaviya, Parash Parajuli and Paul W. Sylvester * College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana 71209, USA Abstract: Cancer cells reprogram their metabolism to meet the demands of accelerated growth. Glucose is the primary source of energy for cancer cells, but under conditions of high-energy demand lipids and free fatty acids become increasingly important. PPAR is a member of the nuclear receptor superfamily and acts to regulate adipocyte differentiation and lipid metabolism. However, in many types of cancer, PPAR activity is elevated in order to increase production of adipogenic factors [1, 2]. -Tocotrienol is an isoform of vitamin E that displays potent anticancer activity [3]. Previous studies have shown that the antiproliferative effects of combined treatment of -tocotrienol with PPAR antagonists was associated with a reduction in PPAR activity, expression of PPAR and RXR, and suppression in Akt activation in MCF-7 and MBA-MB-231 human breast cancer cells [4]. The present study was conducted to determine the effects of combination treatment with these agents on adipogenic factor levels in rapidly proliferating human breast cancer cells. Western blot and qRT-PCR studies showed that combined treatment of -tocotrienol with PPAR antagonists not only suppressed the adipogenic proteins, C/EBP and SREBP-1c, but also decreased their target lipogenic enzymes, ap2, FAS, and HMGCoR. However, treatment effects were also observed in PPAR silenced breast cancer cells, indicating that these effects are mediated through PPAR-independent mechanism. These findings suggest the combined treatment of -tocotrienol with PPAR antagonist may have potential as a therapeutic strategy in the treatment of breast cancer. Keywords: -Tocotrienol, PPAR, Breast Cancer, C/EBP, SREBP-1c, FASN. 1. INTRODUCTION Cancer cells characteristically display an elevated metabolism and consume vast amounts of energy to support their growth and survival. Although, glucose is the primary energy source for cancer cells, during conditions of high-energy demand, lipids and free fatty acids can replace glucose as an important energy source. Adipocytes modulate lipid metabolism and are also involved in activating signaling pathways associated with promoting chronic inflammation [5]. Although it has not yet been firmly established that lipids derived from insulin-resistant adipocytes have a direct impact on cancer cell metabolism, evidence does suggest that activation of adipocytes appears to be involved in supporting growth and proliferation in malignant cells [5]. Peroxisome proliferator activated receptor  (PPAR), a member of the nuclear receptor superfamily, is expressed predominantly in adipose tissue, where it functions to regulates adipocyte differentiation and lipid metabolism [6]. Studies have shown that PPAR levels are elevated in many types of cancer tissues [1, 7, 8]. PPAR may function in cancer cells to increase production of adipogenic factors and lipogenic proteins in support of the high metabolic demands of cancer cells [2, 9]. Therefore, strategies *Address correspondence to this author at the College of Pharmacy, 700 University Avenue, University of Louisiana at Monroe, Monroe, LA 71209, USA; Tel: +1 3183421958; Fax: +1 3183421737; E-mail: sylvester@ulm.edu targeting the inhibition of PPAR may be beneficial in the treatment of cancer by acting to decrease adipogenic proteins and genes in rapidly proliferating cancer cells. PPAR regulates adipogenesis by activating families of transcription factors such as CCAAT- enhancer-binding proteins (C/EBP) and sterol regulatory element binding protein (SREBP; also called ADD1) [10, 11]. Studies have shown that of the three isoforms of C/EBP (C/EBP, C/EBP, and C/EBP), PPAR directly regulates C/EBP and C/EBP to maintain a terminally differentiated state of adipocytes that is absolutely required for the function of fat- selective enhancers such as adipocyte fatty acid binding protein (also called ap2) [12, 13]. In addition, PPAR regulates function of SREBP-1c and SREBP2, which are important regulators of fatty acid uptake and enhance fatty acid (FA) synthesis by modulating activity of key lipogenic enzymes such as FA synthase (FASN) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoR) [14-16]. Investigations have also shown that specific C/EBP and SREBP isoforms are over expressed in many types of cancers in order to compensate for the elevated energy demand displayed by these cells [17, 18]. -Tocotrienol is a naturally occurring isoform within the vitamin E family of compounds that displays potent