Suppression in Mevalonate Synthesis Mediates Antitumor Effects of Combined Statin and γ-Tocotrienol Treatment

• Published in: Lipids 2009-10, Vol.44 (10), p.925-934
• Main Authors: Wali, Vikram B, Bachawal, Sunitha V, Sylvester, Paul W
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Biomedical and Life Sciences; Breast cancer; Cell Line, Tumor; Chromans - administration & dosage; Drug Synergism; Female; HMGR; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Life Sciences; Lipidology; MAPK; Medical Biochemistry; Medicinal Chemistry; Mevalonate; Mevalonic Acid - antagonists & inhibitors; Mevalonic Acid - metabolism; Mice; Mice, Inbred BALB C; Microbial Genetics and Genomics; Neurochemistry; Nutrition; Original Article; p38; Rab6; Rap1A; Statins; Vitamin E; Vitamin E - administration & dosage; Vitamin E - analogs & derivatives; γ‐Tocotrienol
• ISSN: 0024-4201; 1558-9307
• DOI: 10.1007/s11745-009-3344-0

Statins directly inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity, while γ-tocotrienol, an isoform of vitamin E, enhances the degradation and reduces cellular levels of HMGR in various tumor cell lines. Since treatment with statins or γ-tocotrienol alone induced a dose-responsive inhibition, whereas combined treatment with subeffective doses of these agents resulted in a synergistic inhibition in +SA mammary tumor cell growth, studies were conducted to investigate the role of the HMGR pathway in mediating the antiproliferative effects of combined low dose statin and γ-tocotrienol. Treatment with 8 μM simvastatin inhibited cell growth and isoprenylation of Rap1A and Rab6, and supplementation with 2 μM mevalonate reversed these effects. However, the growth inhibitory effects of 4 μM γ-tocotrienol were not dependent upon suppression in mevalonate synthesis. Treatment with subeffective doses of simvastatin (0.25 μM), lovastatin (0.25 μM), mevastatin (0.25 μM), pravastatin (10 μM), or γ-tocotrienol (2 μM) alone had no effect on protein prenylation or mitogenic signaling, whereas combined treatment with these agents resulted in a significant inhibition in +SA cell growth, and a corresponding decrease in total HMGR, Rap1A and Rab6 prenylation, and MAPK signaling, and mevalonate supplementation reversed these effects. These findings demonstrate that the synergistic antiproliferative effects of combined low dose statin and γ-tocotrienol treatment are directly related to an inhibition in HMGR activity and subsequent suppression in mevalonate synthesis.