First Evidence That g-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-kB Pathway

Kanjoormana A. Manu1, Muthu K. Shanmugam1, Lalitha Ramachandran1, Feng Li1, Chee Wai Fong3, Alan Prem Kumar1,2,6, Patrick Tan2,4,5, and Gautam Sethi1,2

1Department of Pharmacology, Yong Loo Lin School of Medicine,
2Cancer Science Institute of Singapore, National University of Singapore;
3Davos Life Science Pte Ltd;
4Genome Institute of Singapore; and
5Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; and
6School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Perth, Western Australia
Note: K.A. Manu and M.K. Shanmugam contributed equally to this work.

Clin Cancer Res; 18(8) April 15, 2012
doi: 10.1158/1078-0432.CCR-11-2470
2012 American Association for Cancer Research
Published Online First February 20, 2012

Abstract:

Purpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether g-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.
Experimental Design: The effect of g-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-kB activation by DNA-binding assay, and gene expression by Western blotting. The effect of g-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.
Results: g-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-kB, and suppressed the NF-kB–regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of g-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and g-tocotrienol. As compared with vehicle control, g-tocotrienol also suppressed the NF-kB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.
Conclusions: Overall our results show that g-tocotrienol can potentiate the effects of capecitabine through suppression of NF-kB–regulated markers of proliferation, invasion, angiogenesis, and metastasis.

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