title: G31P, CXCR1/2 inhibitor, with cisplatin inhibits the growth of mice hepatocellular carcinoma and mitigates high‑dose cisplatin-induced nephrotoxicity.
abstract: Cisplatin (DDP), a cytotoxic antitumor drug, functions in a dose-dependent manner. However, the pursuit for high‑dose therapeutic effects leads to more serious side effects including kidney toxicity. Nephrotoxicity caused due to endothelial cell dysfunction and neutrophils infiltration in kidneys. Interleukin-8 (IL-8) is an ELR+ chemokine binds with CXCR1/2 receptors and its role is primarily in neutrophils recruitment and also involved in invasion, angiogenesis and metastasis of different solid tumors including liver cancer. G31P, a CXCR1/2 antagonist, binds with CXCR1/2 with high affinity, and acts as an anti-inflammatory and antitumor agent. In the present study, we examined the antitumor effects of G31P and DDP on mouse liver cancer cells, and the effects exerted by G31P on cisplatin-induced renal injury. In vitro, effects of the G31P and DDP regimen on H22 cell proliferation were investigated by MTT assay. In vivo BALB/c mice were inoculated subcutaneously with 1x106 H22 cells and treated after one week with a high single dose of DDP with and without G31P on alternative days until the experiment was terminated. On the 15th day the mice were sacrificed, dissected and kidney tissues were analyzed using H&E staining. Myeloperoxidase (MPO) activity was assessed and RT-PCR was performed to detect inflammatory cytokines. Solid tumors were weighed for tumor growth and performed pathological examination, immunohistochemistry and western blotting were performed to detect tissue-related protein expressions in tumor tissue. The tumor inhibitory rate of DDP, G31P and DDP+G31P groups was 38.40, 40.74 and 74.80%, respectively, and the general state of mice in the DDP+G31P group was significantly improved as compared to the DDP group. The results indicated that G31P with DDP significantly inhibited the proliferation while the growth of H22 cell carnimona in vitro and in vivo enhanced the efficacy of cisplatin in cancer treatment with reduced side effects on acute renal failure.
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Muhammad Noman
authors.initials: MN
authors.lastname: Khan
authors.affiliation: Jilin Medical College, Jilin 132013, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu 300, Taiwan, R.O.C.
authors.forename: Jya-Wei
authors.initials: JW
authors.lastname: Cheng
authors.affiliation: The Division of Respirology, Critical Care and Sleep Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Gordon
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D016209:Interleukin-8 / Q000008:administration & dosage* / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C457773:CXCL8(3-73)K11R,G31P, bovine; D016207:Cytokines; D016209:Interleukin-8; D010446:Peptide Fragments; D002945:Cisplatin