Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2014-03, Vol.92 (3), p.267-276
• Main Authors: Manu, Kanjoormana A., Shanmugam, Muthu K., Li, Feng, Chen, Luxi, Siveen, Kodappully Sivaraman, Ahn, Kwang Seok, Kumar, Alan Prem, Sethi, Gautam
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Capecitabine; Cell Line, Tumor; Cell Proliferation - drug effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Disease Models, Animal; DNA - metabolism; Female; Fluorouracil - analogs & derivatives; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Gene Expression Regulation, Neoplastic - drug effects; Human Genetics; Humans; Immunohistochemistry; Internal Medicine; Mice; Mice, Nude; Molecular Medicine; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; NF-kappa B - metabolism; Original Article; Protein Binding - drug effects; Simvastatin - chemistry; Simvastatin - pharmacology; Simvastatin - therapeutic use; Stomach Neoplasms - blood supply; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Xenograft Model Antitumor Assays
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-013-1095-0

Chemoresistance remains a major problem in the treatment of gastric cancer patients. Hence, novel pharmacological agents that can overcome drug resistance are urgently required. Whether simvastatin can sensitize the gastric cancer to the antitumor effects of capecitabine in vitro and in vivo was investigated. The effect of simvastatin on the proliferation of gastric cancer cells was examined by mitochondrial dye-uptake 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, apoptosis by esterase staining, NF-κB activation by DNA binding assay, and protein expression by western blot analysis. The effect of simvastatin on the tumor growth in xenograft mouse model of human gastric cancer was also examined. Simvastatin suppressed the proliferation of gastric cancer cells, enhanced the apoptotic effects of capecitabine, suppressed the constitutive activation of NF-κB, and abrogated the expression of cyclooxygenase-2 (COX-2), cyclin D1, Bcl-2, survivin, CXC motif receptor 4, and MMP-9 proteins. In a xenograft mouse model, we observed that the administration of simvastatin alone (5 mg/kg body weight, intraperitoneal thrice/week) significantly suppressed the growth of the tumor and this effect was further potentiated by capecitabine treatment. As compared to the vehicle control, simvastatin also suppressed the expression of NF-κB-regulated gene products such as cyclin D1, COX-2, ICAM-1, MMP-9, survivin, Bcl-xL, and XIAP in tumor tissues. Overall, our results demonstrate that simvastatin can enhance the effects of capecitabine through suppression of NF-κB-regulated markers of proliferation, invasion, angiogenesis, and metastasis. Key message Simvastatin suppressed the proliferation and augmented apoptotic effects of capecitabine. Simvastatin suppressed constitutive activation of NF-κB and its regulated genes. Simvastatin enhanced the tumor growth inhibitory effects of capecitabine.