d-δ-Tocotrienol-mediated suppression of the proliferation of human PANC-1, MIA PaCa-2, and BxPC-3 pancreatic carcinoma cells

Pancreas. 2009 May;38(4):e124-36. doi: 10.1097/MPA.0b013e3181a20f9c.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology
  • Adenocarcinoma / physiopathology
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / physiopathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Flow Cytometry
  • G1 Phase / drug effects
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Lovastatin / pharmacology
  • Mevalonic Acid / pharmacology
  • Microscopy, Fluorescence
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / physiopathology
  • Tocotrienols / pharmacology*

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Tocotrienols
  • Lovastatin
  • Mevalonic Acid