Parajuli Parash, Tiwari Roshan Vijay, Sylvester Paul William
School of Pharmacy, University of Louisiana at Monroe.
Biol Pharm Bull. 2015;38(9):1352-60. doi: 10.1248/bpb.b15-00306.
Aerobic glycolysis is an established hallmark of cancer. Neoplastic cells display increased glucose consumption and a corresponding increase in lactate production compared to the normal cells. Aerobic glycolysis is regulated by the phosphatidylinositol-3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling pathway, as well as by oncogenic transcription factors such as c-Myc and hypoxia inducible factor 1α (HIF-1α). γ-Tocotrienol is a natural isoform within the vitamin E family of compounds that displays potent antiproliferative and apoptotic activity against a wide range of cancer cell types at treatment doses that have little or no effect on normal cell viability. Studies were conducted to determine the effects of γ-tocotrienol on aerobic glycolysis in mouse +SA and human MCF-7 breast cancer cells. Treatment with γ-tocotrienol resulted in a dose-responsive inhibition of both +SA and MCF-7 mammary tumor cell growth, and induced a relatively large reduction in glucose utilization, intracellular ATP production and extracellular lactate excretion. These effects were also associated with a large decrease in enzyme expression levels involved in regulating aerobic glycolysis, including hexokinase-II, phosphofructokinase, pyruvate kinase M2, and lactate dehydrogenase A. γ-Tocotrienol treatment was also associated with a corresponding reduction in the levels of phosphorylated (active) Akt, phosphorylated (active) mTOR, and c-Myc, but not HIF-1α or glucose transporter 1 (GLUT-1). In summary, these findings demonstrate that the antiproliferative effects of γ-tocotrienol are mediated, at least in the part, by the concurrent inhibition of Akt/mTOR signaling, c-Myc expression and aerobic glycolysis.
有氧糖酵解是癌症的一个既定标志。与正常细胞相比，肿瘤细胞表现出葡萄糖消耗增加以及乳酸生成相应增加。有氧糖酵解受磷脂酰肌醇-3-激酶（PI3K）/Akt/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路调控，同时也受致癌转录因子如c-Myc和缺氧诱导因子1α（HIF-1α）调控。γ-生育三烯酚是维生素E类化合物中的一种天然异构体，在对正常细胞活力影响很小或无影响的治疗剂量下，对多种癌细胞类型具有强大的抗增殖和凋亡活性。开展了多项研究以确定γ-生育三烯酚对小鼠+SA和人MCF-7乳腺癌细胞有氧糖酵解的影响。用γ-生育三烯酚处理导致+SA和MCF-7乳腺肿瘤细胞生长受到剂量依赖性抑制，并使葡萄糖利用、细胞内ATP生成和细胞外乳酸排泄相对大幅减少。这些作用还与调节有氧糖酵解的酶表达水平大幅降低有关，这些酶包括己糖激酶-II、磷酸果糖激酶、丙酮酸激酶M2和乳酸脱氢酶A。γ-生育三烯酚处理还与磷酸化（活性）Akt、磷酸化（活性）mTOR和c-Myc水平相应降低有关，但与HIF-1α或葡萄糖转运蛋白1（GLUT-1）无关。总之，这些发现表明，γ-生育三烯酚的抗增殖作用至少部分是通过同时抑制Akt/mTOR信号传导、c-Myc表达和有氧糖酵解介导的。
