d-δ-tocotrienol-mediated suppression of the proliferation of human PANC-1, MIA PaCa-2, and BxPC-3 pancreatic tumor cells
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The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation or dolichylation of numerous growth-related proteins including nuclear lamins Ras and growth factor receptors. Competitive inhibitors of HMG CoA reductase, the statins, and down-regulators of HMG CoA reductase, the monoterpene geraniol and the sesquitepene farnesol, have been shown to suppress pancreatic tumor growth both in vitro and in vivo by inducing cell cycle arrest and initiating apoptosis. d-δ-Tocotrienol, a vitamin E isomer with a farnesol moiety, has been shown to be growth-suppressive in a number of in vitro and in vivo tumor models. These considerations led to an in vitro evaluation of the tumor-suppressive impact of d-δ-tocotrienol in human MIA PaCa-2 and PANC-1 pancreas carcinoma cells and BxPC-3 pancreas ductal adenocarcinoma cells. d-δ-Tocotrienol induced concentration-dependent suppression of the proliferation of all three cell lines with 50% inhibitory concentrations of 28 ± 6, 35 ± 8, and 35 ± 7 µmol/L for MIA PaCa-2, PANC-1, and BxPC-3, respectively. Cell cycle analyses revealed d-δ-tocotrienol induced Gl arrest in MIA PaCa-2, PANC-1 and BxPC-3 cells. d-δ-Tocotrienol-mediated morphological changes resemble those occurring in apoptotic cells. d-δ-Tocotrienol also induced apoptosis in all three types of pancreatic tumor cells by flow cytometric analysis and fluorescence microscopy. A blend of lovastatin (2 µmol/L) and d-δ-tocotrienol (5 and 10 µmol/L) synergistically suppressed the proliferation of MIA PaCa-2 cells. Supplemental mevalonate attenuated the growth inhibition induced by d-δ-tocotrienol in all three types of pancreatic tumor cells tested. The results of these studies suggested that d-δ-tocotrienol as a down-regulator of the mevalonate pathway may have potential as an adjuvant therapy in pancreatic cancer.