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

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 inv...

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Main Authors:	Manu, K., Shanmugam, M., Li, F., Chen, L., Siveen, K., Ahn, K., Kumar, Alan Prem, Sethi, G.
Format:	Journal Article
Published:	Springer 2013
Subjects:	Simvastatin Apoptosis Chemoresistance Gastric cancer NF-?B
Online Access:	http://hdl.handle.net/20.500.11937/21839

id	curtin-20.500.11937-21839
recordtype	eprints
spelling	curtin-20.500.11937-218392018-03-29T09:06:35Z Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products Manu, K. Shanmugam, M. Li, F. Chen, L. Siveen, K. Ahn, K. Kumar, Alan Prem Sethi, G. Simvastatin Apoptosis Chemoresistance Gastric cancer NF-?B 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 dyeuptake 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, apoptosis by esterase staining, NF-?B 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 ofNF-?B, 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-?B-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-?B-regulated markers of proliferation, invasion, angiogenesis, and metastasis. 2013 Journal Article http://hdl.handle.net/20.500.11937/21839 10.1007/s00109-013-1095-0 Springer restricted
repository_type	Digital Repository
institution_category	Local University
institution	Curtin University Malaysia
building	Curtin Institutional Repository
collection	Online Access
topic	Simvastatin Apoptosis Chemoresistance Gastric cancer NF-?B
spellingShingle	Simvastatin Apoptosis Chemoresistance Gastric cancer NF-?B Manu, K. Shanmugam, M. Li, F. Chen, L. Siveen, K. Ahn, K. Kumar, Alan Prem Sethi, G. Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products
description	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 dyeuptake 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, apoptosis by esterase staining, NF-?B 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 ofNF-?B, 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-?B-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-?B-regulated markers of proliferation, invasion, angiogenesis, and metastasis.
format	Journal Article
author	Manu, K. Shanmugam, M. Li, F. Chen, L. Siveen, K. Ahn, K. Kumar, Alan Prem Sethi, G.
author_facet	Manu, K. Shanmugam, M. Li, F. Chen, L. Siveen, K. Ahn, K. Kumar, Alan Prem Sethi, G.
author_sort	Manu, K.
title	Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products
title_short	Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products
title_full	Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products
title_fullStr	Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products
title_full_unstemmed	Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products
title_sort	simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa b-regulated gene products
publisher	Springer
publishDate	2013
url	http://hdl.handle.net/20.500.11937/21839
first_indexed	2018-09-06T20:22:19Z
last_indexed	2018-09-06T20:22:19Z
_version_	1610890965080342528

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

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