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

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Abstract

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.

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Acknowledgments

This work was supported by grant from National Medical Research Council of Singapore [R-184-000-211-213] to GS. APK was supported by grants from Singapore Ministry of Education Tier 2 [MOE2012-T2-2-139], Academic Research Fund Tier 1 [R-184-000-228-112], and Cancer Science Institute of Singapore, Experimental Therapeutics I Program [Grant R-713-001-011-271].

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Kanjoormana A. Manu, Muthu K. Shanmugam, Feng Li, Luxi Chen, Kodappully Sivaraman Siveen, Alan Prem Kumar & Gautam Sethi

  2. Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore, 117599, Singapore

    Luxi Chen, Alan Prem Kumar & Gautam Sethi

  3. College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Kwang Seok Ahn

  4. School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Western Australia, 6009, Australia

    Alan Prem Kumar

  5. Department of Biological Sciences, University of North Texas, Denton, TX, 76203, USA

    Alan Prem Kumar

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  1. Kanjoormana A. Manu
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  2. Muthu K. Shanmugam
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  3. Feng Li
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  7. Alan Prem Kumar
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  8. Gautam Sethi
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Correspondence to Gautam Sethi.

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Both KAM and MKS contributed equally to this work.

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Manu, K.A., Shanmugam, M.K., Li, F. et al. Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products. J Mol Med 92, 267–276 (2014). https://doi.org/10.1007/s00109-013-1095-0

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  • DOI: https://doi.org/10.1007/s00109-013-1095-0

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