Anticancer Effects of γ-Tocotrienol Are Associated with a Suppression in Aerobic Glycolysis.

Abstract

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.

• Authors: Parash Parajuli, Roshan Vijay Tiwari, Paul William Sylvester
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 38 Issue 9 Pg. 1352-60 ( 2015) ISSN: 1347-5215 [Electronic] Japan
• PMID: 26328490 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chromans
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• Vitamin E
• Lactic Acid
• plastochromanol 8
• Adenosine Triphosphate
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Glucose

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chromans (pharmacology)
• Glucose (metabolism)
• Glycolysis (drug effects)
• Humans
• Lactic Acid (metabolism)
• MCF-7 Cells
• Mice
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Vitamin E (analogs & derivatives, pharmacology)