The angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer

Mitsuyoshi Okazaki; Sachio Fushida; Shinichi Harada; Tomoya Tsukada; Jun Kinoshita; Katsunobu Oyama; Hidehiro Tajima; Itasu Ninomiya; Takashi Fujimura; Tetsuo Ohta

doi:10.1016/j.canlet.2014.09.019

The angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer

Cancer Lett. 2014 Dec 1;355(1):46-53. doi: 10.1016/j.canlet.2014.09.019. Epub 2014 Sep 16.

Affiliations

¹ Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa Ishikawa 920-8641, Japan.
² Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa Ishikawa 920-8641, Japan. Electronic address: [email protected].
³ Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Kanazawa Ishikawa 920-8641, Japan.

PMID: 25224569
DOI: 10.1016/j.canlet.2014.09.019

Abstract

Gastric cancer with peritoneal dissemination has poor clinical prognosis because of the presence of rich stromal fibrosis and acquired drug resistance. Recently, Angiotensin II type I receptor blockers such as candesartan have attracted attention for their potential anti-fibrotic activity. We examined whether candesartan could attenuate tumor proliferation and fibrosis through the interaction between gastric cancer cell line (MKN45) cells and human peritoneal mesothelial cells. Candesartan significantly reduced TGF-β1 expression and epithelial-to-mesenchymal transition-like change, while tumor proliferation and stromal fibrosis were impaired. Targeting the Angiotensin II signaling pathway may therefore be an efficient strategy for treatment of tumor proliferation and fibrosis.

Keywords: Angiotensin II; Fibrosis; Gastric cancer; Peritoneal dissemination; TGF-β.

MeSH terms

Angiotensin II Type 1 Receptor Blockers / pharmacology*
Animals
Antineoplastic Agents / pharmacology*
Benzimidazoles / pharmacology*
Biphenyl Compounds
Cell Line, Tumor
Cell Proliferation / drug effects*
Dose-Response Relationship, Drug
Epithelial-Mesenchymal Transition / drug effects
Female
Fibrosis
Humans
Mice, Inbred BALB C
Mice, Nude
Omentum / drug effects
Omentum / metabolism
Omentum / pathology
Receptor, Angiotensin, Type 1 / drug effects*
Receptor, Angiotensin, Type 1 / metabolism
Signal Transduction / drug effects
Stomach Neoplasms / drug therapy*
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology
Stromal Cells / drug effects
Stromal Cells / metabolism
Stromal Cells / pathology
Tetrazoles / pharmacology*
Time Factors
Transforming Growth Factor beta1 / metabolism
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

AGTR1 protein, human
Angiotensin II Type 1 Receptor Blockers
Antineoplastic Agents
Benzimidazoles
Biphenyl Compounds
Receptor, Angiotensin, Type 1
TGFB1 protein, human
Tetrazoles
Transforming Growth Factor beta1
candesartan