d-δ-Tocotrienol-mediated suppression of the proliferation of human PANC-1, MIA PaCa-2, and BxPC-3 pancreatic carcinoma cells.
OBJECTIVE
The rate-limiting activity of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides intermediates essential for growth. Competitive inhibitors of HMG CoA reductase, such as the statins, and down-regulators of reductase, such as the tocotrienols, suppress tumor growth. We evaluated the impact of d-delta-tocotrienol, the most potent vitamin E isomer, on human MIA PaCa-2 and PANC-1 pancreatic carcinoma cells and BxPC-3 pancreatic ductal adenocarcinoma cells.


METHODS
Cell proliferation was measured by using CellTiter 96 Aqueous One Solution (Promega, Madison, Wis). Cell cycle distribution was determined by flow cytometry. Apoptosis was evaluated by Annexin V staining and fluorescence microscopy after dual staining with acridine orange and ethidium bromide.


RESULTS
d-delta-Tocotrienol induced concentration-dependent suppression of cell proliferation with 50% inhibitory concentrations of 28 (6) micromol/L (MIA PaCa-2), 35 (7) micromol/L (PANC-1), and 35 (8) microL (BxPC-3), respectively. These effects are attributable to cell cycle arrest at the G1 phase and apoptosis. Mevalonate attenuated d-delta-tocotrienol-mediated growth inhibition. A physiologically attainable blend of d-delta-tocotrienol and lovastatin synergistically suppressed the proliferation of MIA PaCa-2 cells.


CONCLUSIONS
Suppression of mevalonate pathway activities, be it by modulators of HMG CoA reductase (statins, tocotrienols, and farnesol), farnesyl transferase (farnesyl transferase inhibitors), and/or mevalonate pyrophosphate decarboxylase (phenylacetate) activity, may have a potential in pancreatic cancer chemotherapy.
Department of Nutrition and Food Sciences, Texas Woman's University, Denton, TX 76204, USA.
Deema
D
Hussein
Huanbiao
H
Mo
D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology; D024508:Tocotrienols / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D024508:Tocotrienols; D008148:Lovastatin; D008798:Mevalonic Acid