title: 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.
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.
authors: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Junpu
authors: J
authors: Wang
authors: Department of Pathology, School of Basic Medicine, Third Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Wanming
authors: W
authors: Hu
authors: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Kuansong
authors: K
authors: Wang
authors: Department of Neurology, Third Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Jun
authors: J
authors: Yu
authors: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Baihua
authors: B
authors: Luo
authors: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Gengqiu
authors: G
authors: Luo
authors: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Weiyuan
authors: W
authors: Wang
authors: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Huiling
authors: H
authors: Wang
authors: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Jinghe
authors: J
authors: Li
authors: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors: Jifang
authors: J
authors: Wen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; D002945:Cisplatin; D005472:Fluorouracil; C490707:reparixin