title: First evidence that γ-tocotrienol inhibits the growth of human gastric cancer and chemosensitizes it to capecitabine in a xenograft mouse model through the modulation of NF-κB pathway.
abstract: OBJECTIVE
  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 γ-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.
  
  
  METHODS
  The effect of γ-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and gene expression by Western blotting. The effect of γ-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.
  
  
  RESULTS
  γ-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-κB, and suppressed the NF-κB-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 γ-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 γ-tocotrienol. As compared with vehicle control, γ-tocotrienol also suppressed the NF-κB 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 γ-tocotrienol can potentiate the effects of capecitabine through suppression of NF-κB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, Cancer Science Institute of Singapore, National University of Singapore.
authors.forename: Kanjoormana A
authors.initials: KA
authors.lastname: Manu
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.forename: Lalitha
authors.initials: L
authors.lastname: Ramachandran
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Chee Wai
authors.initials: CW
authors.lastname: Fong
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D000069287:Capecitabine; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000378:metabolism / Q000494:pharmacology*; D019938:Cyclin D1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: C494812:Bcl2l1 protein, mouse; C117749:Birc5 protein, mouse; C527276:CXCR4 protein, human; D002839:Chromans; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019253:Proto-Oncogene Proteins c-bcl-2; D019718:Receptors, CXCR4; D012097:Repressor Proteins; D000077022:Survivin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; D003841:Deoxycytidine; D018799:Intercellular Adhesion Molecule-1; D019938:Cyclin D1; D014810:Vitamin E; C013649:plastochromanol 8; D000069287:Capecitabine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020780:Matrix Metalloproteinase 9; D005472:Fluorouracil