Background: The applicability of nutraceutical therapy with natural tocotrienols to treatment of cancer in experimental models has been recently shown in breast, prostate, colorectal, skin, lung, and gastric cancers. To identify the best natural tocotrienol for nutraceutical therapy of human pancreatic cancer, we have done comparative evaluation of the four natural tocotrienols (\#945;, \#946;, \#947; and \#948;-tocotrienol) in in vitro and in vivo models of human pancreatic cancer. Methods: The antiproliferative (MTT assay) and proapoptotic (Death ELISA assay) activity of \#945;, \#946;, \#947; and \#948;-tocotrienol was evaluated in immortalized normal human pancreatic ductal epithelial cells (HPDE C7), HPDE cells transformed with oncogenic Kras (C7-Kras), as well as human pancreatic cancer cell lines MiaPaCa-2 and AsPc-1. The effect of the tocotrienol compounds on malignant transformation in MiaPaca-2 cells was determined by colony formation assay. The in vivo activity of the tocotrienol compounds following oral administration was evaluated in SCID nude mice xenografted with human pancreatic cancer AsPc-1 cells. Because the nuclear factor-\#954;B (NF-\#954;B) pathway has a central role in human pancreatic tumorigenesis, we investigated the comparative effect of the tocotrienol compounds on the NF-\#954;B pathway in vitro and in vivo. Results: \#948;-Tocotrienol showed superior antitumor activity compared to \#945;-, \#946;-, and \#947;-tocotrienols in vitro and in vivo. \#948;-tocotrienol inhibited the cell growth of transformed C7-Kras, and pancreatic cancer cells (MiaPaCa-2 and AsPc-1) in a concentration and time-dependent manner but had no effect on HPDE cells. Malignant transformation was inhibited by 70, 30, 19 and 6% with \#948;, \#947;, \#946; and \#945;-tocotrienol, respectively in MiaPaca-2 cells. The IC50 for \#948;, \#947;, \#946; and \#945;-tocotrienol in MiaPaCa-2 cells were 40, 45, 60 and >100 µM, respectively. The apoptosis induction was 96, 30, 13 and 6% with \#948;, \#947;, \#946; and \#945;-tocotrienol, respectively at 50 µM concentrations. In vivo AsPc-1 tumor growth was inhibited by 46, 37, 14 and 0% with \#948;, \#947;, \#946; and \#945;-tocotrienol treatment. Nuclear DNA binding of NF-\#954;B/p65 activity, p65/p50 subunits, p-I\#954;B\#945;, antiapototic proteins Bcl-xL and survivin were inhibited by \#948; and \#947;-tocotrienol in cell lines and tumor tissues. Also, \#948;-tocotrienol induced more Caspase 3 activity and PARP-1 cleavage, as well as CK18 and Bax expression than \#947; and \#946;-tocotrienols in cell lines and tumor tissues. Conclusion: Comparative evaluation of tocotrienols as potential antitumor agents for pancreatic cancer strongly suggests that \#948;-tocotrienol is the most bioactive tocotrienol. \#948;-Tocotrienol inhibited the NF-\#954;B pathway, leading to down-regulation of antiapoptotic proteins and up-regulation of proapoptotic proteins. These data support the investigation of \#948;-tocotrienol as a potential chemopreventive and therapeutic agent against pancreatic cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 964.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO