Repertaxin, an inhibitor of the chemokine receptors CXCR1 and CXCR2, inhibits malignant behavior of human gastric cancer MKN45 cells in vitro and in vivo and enhances efficacy of 5-fluorouracil

Wang,Junpu; Hu,Wanming; Wang,Kuansong; Yu,Jun; Luo,Baihua; Luo,Gengqiu; Wang,Weiyuan; Wang,Huiling; Li,Jinghe; Wen,Jifang

doi:10.3892/ijo.2016.3371

Repertaxin, an inhibitor of the chemokine receptors CXCR1 and CXCR2, inhibits malignant behavior of human gastric cancer MKN45 cells in vitro and in vivo and enhances efficacy of 5-fluorouracil

Authors:
- Junpu Wang
- Wanming Hu
- Kuansong Wang
- Jun Yu
- Baihua Luo
- Gengqiu Luo
- Weiyuan Wang
- Huiling Wang
- Jinghe Li
- Jifang Wen
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Affiliations: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China, Department of Pathology, School of Basic Medicine, Third Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China, Department of Neurology, Third Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China
Published online on: February 2, 2016 https://doi.org/10.3892/ijo.2016.3371
Pages: 1341-1352
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chemokine-mediated activation of G protein-coupled receptors CXCR1/2 promotes tumor growth, invasion, inflammation and metastasis. Repertaxin, a CXCR1/2 small-molecule inhibitor, has been shown to attenuate many of these tumor-associated processes. The present study aimed to investigate the effects of repertaxin alone and in combination with 5-fluorouracil (5-FU) on the malignant behavior of gastric cancer and the potential mechanisms. Gastric cancer MKN45 cells were treated in vitro with repertaxin and 5-FU, either alone or in combination. MTT and colony formation assay were performed to assess proliferation. Cell cycle progression and apoptosis was completed by flow cytometry. Migration and invasion were also assessed by transwell and wound-healing assay. Western blot analysis and quantitative RT-PCR were performed to determine expression of signaling molecules. MKN45 cells were also grown as xenografts in nude mice. Mice were treated with repertaxin and 5-FU, and tumor volume and weight, angiogenesis, proliferation and apoptosis were monitored. Combination of repertaxin and 5-FU inhibited MKN45 cell proliferation and increased apoptosis better than either agent alone. Similarly, enhanced effect of the combination was also observed in migration and invasion assays. The improved effect of repertaxin and 5-FU was also observed in vivo, as xenograft models treated with both compounds exhibited significantly decreased tumor volume and increased apoptosis. In conclusion, repertaxin inhibited malignant behavior of human gastric cancer MKN45 cells in vitro and in vivo and enhances efficacy of 5-fluorouracil. These data provide rationale that targeting CXCR1/2 with small molecule inhibitors may enhance chemotherapeutic efficacy for the treatment of gastric cancer.

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