Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

Yao Song; Tomohisa Baba; Ying-Yi Li; Kaoru Furukawa; Yamato Tanabe; Seiichi Matsugo; Soichiro Sasaki; Naofumi Mukaida

doi:10.1016/j.bbrc.2015.01.112

Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

Biochem Biophys Res Commun. 2015 Mar 6;458(2):341-6. doi: 10.1016/j.bbrc.2015.01.112. Epub 2015 Jan 31.

Authors

Yao Song¹, Tomohisa Baba¹, Ying-Yi Li², Kaoru Furukawa³, Yamato Tanabe³, Seiichi Matsugo⁴, Soichiro Sasaki¹, Naofumi Mukaida⁵

Affiliations

¹ Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
² Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ 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.
⁴ School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa, Japan.
⁵ Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: mukaida@staff.kanazawa-u.ac.jp.

PMID: 25646691
DOI: 10.1016/j.bbrc.2015.01.112

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.

Keywords: CXCL8; Chemo-resistance; Gemcitabine; Pancreatic cancer.

MeSH terms

Animals
Antimetabolites, Antineoplastic / administration & dosage
Antimetabolites, Antineoplastic / adverse effects
Cell Line, Tumor
Cell Proliferation / drug effects
Deoxycytidine / administration & dosage
Deoxycytidine / adverse effects
Deoxycytidine / analogs & derivatives*
Dose-Response Relationship, Drug
Gemcitabine
Gene Expression Regulation, Neoplastic / drug effects
Humans
Interleukin-8 / metabolism*
Mice
Mice, Inbred BALB C
Mice, Nude
NF-kappa B / metabolism
Neovascularization, Pathologic / chemically induced*
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / metabolism*
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology
Reactive Oxygen Species / metabolism
Treatment Outcome
Up-Regulation / drug effects

Substances

Antimetabolites, Antineoplastic
CXCL8 protein, human
Interleukin-8
NF-kappa B
Reactive Oxygen Species
Deoxycytidine
Gemcitabine