title: Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization.
abstract: Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization.
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors: Yao
authors: Y
authors: Song
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors: Tomohisa
authors: T
authors: Baba
authors: Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Ying-Yi
authors: YY
authors: Li
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan; School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors: Kaoru
authors: K
authors: Furukawa
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan; School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors: Yamato
authors: Y
authors: Tanabe
authors: School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors: Seiichi
authors: S
authors: Matsugo
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors: Soichiro
authors: S
authors: Sasaki
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: mukaida@staff.kanazawa-u.ac.jp.
authors: Naofumi
authors: N
authors: Mukaida
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C508606:CXCL8 protein, human; D016209:Interleukin-8; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: CXCL8; Chemo-resistance; Gemcitabine; Pancreatic cancer