Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression.
OBJECTIVE
Previous studies have shown that gamma-tocotrienol induces potent anti-proliferative effects on +SA mammary tumour cells in culture; here, investigations have been conducted to determine its effects on intracellular signalling proteins involved in regulating cell cycle progression.


METHODS
+SA cells were maintained in mitogen-free defined media containing 0 or 4 micromgamma-tocotrienol, for 48 h to synchronize cell cycle in G(0) phase, and then they were exposed to 100 ng/ml EGF to initiate cell cycle progression. Whole cell lysates were collected at various time points from each treatment group and were prepared for Western blot analysis.


CONCLUSIONS
Treatment with 4 micromgamma-tocotrienol significantly inhibited +SA cell proliferation over a 4-day culture period. Moreover, this treatment resulted in a relatively large reduction in cyclin D1, cyclin dependent kinase (CDK)4, CDK2 and CDK6 levels, between 4 and 24 h after EGF exposure. Tocotrienol treatment also resulted in a relatively large increase in CDK inhibitor (CKI) p27, prior to and after EGF exposure, but had little effect on levels of CKIs, p21 and p15. Tocotrienol treatment also induced a large relative reduction in retinoblastoma (Rb) protein phosphorylation at ser780 and ser807/811. These findings strongly suggest that anti-proliferative effects of gamma-tocotrienol are associated with reduction in cell cycle progression from G(1) to S, as evidenced by increased p27 levels, and a corresponding decrease in cyclin D1, CDK2, CDK4, CDK6 and phosphorylated Rb levels.
Samant
G V
GV
College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
Wali
V B
VB
Sylvester
P W
PW
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D016192:Resting Phase, Cell Cycle; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D002839:Chromans; D019938:Cyclin D1; D014810:Vitamin E; D050760:Cyclin-Dependent Kinase Inhibitor p27; C013649:plastochromanol 8; D004815:Epidermal Growth Factor; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6