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Synergistic Antiproliferative Effects of γ‐Tocotrienol and Statin Treatment on Mammary Tumor Cells
Author(s) -
Wali Vikram B.,
Sylvester Paul W.
Publication year - 2007
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-007-3102-0
Subject(s) - lipidology , clinical chemistry , tocotrienol , statin , simvastatin , cancer research , pharmacology , medicine , chemistry , tocopherol , biochemistry , vitamin e , antioxidant
Statins are potent inhibitors of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMGCoA) reductase and display anticancer activity, but their clinical use is limited by their high‐dose toxicity. Similarly, γ‐tocotrienol, an isoform of vitamin E, also reduces HMGCoA reductase activity and displays potent anticancer activity. Studies were conducted to determine if combined low dose treatment of γ‐tocotrienol with individual statins resulted in a synergistic antiproliferative effect on neoplastic mouse +SA mammary epithelial cells. Treatment with 3–4 μM γ‐tocotrienol or 2–8 μM simvastatin, lovastatin or mevastatin alone resulted in a significant decrease, whereas treatment with 10–100 μM pravastatin had no effect on +SA cell growth. However, combined treatment of subeffective doses (0.25 or 10 μM) of individual statins with 0.25–2.0 μM γ‐tocotrienol resulted in a dose‐responsive synergistic inhibition in +SA cell proliferation. Additional studies showed that treatment with subeffective doses of individual statins or γ‐tocotrienol alone had no effect, whereas combined treatment of these compounds resulted in a relatively large decrease in intracellular levels of phosphorylated (activated) MAPK, JNK, p38, and Akt. These findings strongly suggest that combined low dose treatment of γ‐tocotrienol with individual statins may have potential value in the treatment of breast cancer without causing myotoxicity that is associated with high dose statin treatment.