Synergistic Antiproliferative Effects of Combinedγ-Tocotrienol and PPARγAntagonist Treatment Are Mediated through PPARγ-Independent Mechanisms in Breast Cancer Cells

Abstract

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-PGJ2, 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.

Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review

“…The contradictory results might be derived from the cancer cell types used in this experiment; the authors [26] employed breast cancer cells while Campbell et al [79] used prostate cancer cells. They concluded that the synergistic effect between γ-T3 and PPARγ antagonists was mediated through PPARγ-independent mechanisms [80]. …”

Role of Autophagy in Mediating the Anticancer Effects of Tocotrienols

“…Thus, tocotrienol displays potent anticancer activity at treatment doses that have little or no effect on the growth and viability of primary epithelial cells isolated from the mammary gland or immortalized mouse (CL-S1) and human (MCF-10A) normal mammary epithelial cell lines [16][17][18]. Additional reports have shown that the combined use of tocotrienols with other chemotherapeutic agents results in a synergistic anticancer response [19][20][21][22][23].…”

“…Furthermore, the use of phytochemicals in the prevention and treatment of cancer has recently gained much interest, and combination therapies are attractive because an additive or synergistic therapeutic response can result. The rationale for using tocotrienols in combination therapy is based on the findings that a form of vitamin E has a broad range of anticancer actions and the principle that resistance to any single agent can be overcome by using multiple agents with complimentary mechanisms of action [11,12,[19][20][21][22][23]40]. Previous studies have shown that combined low dose of γ-tocotrienol with other chemotherapeutic or phytochemical agents displays significantly enhanced anticancer effects, as compared to that of individual treatment alone [11].…”

The update on transcriptional regulation of autophagy in normal and pathologic cells: A novel therapeutic target

“…PPAR gamma is also present in other tissues, such as breast [70,71], colon [72][73][74], lung [75,76], ovary [77,78], prostate [79,80] and thyroid [81,82] wherein it mediates several specific functions, such as early development [83], cell proliferation [84], differentiation [85], apoptosis [86], and metabolic homeostasis [87]. Many investigators [88][89][90][91][92][93][94][95][96][97] reported that PPAR gamma was also involved in the control of transcriptional regulation of autophagy.…”