HA1077, a Rho kinase inhibitor, suppresses glioma‐induced angiogenesis by targeting the Rho‐ROCK and the mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase (MEK/ERK) signal pathways

• Published in: Cancer science 2011-02, Vol.102 (2), p.393-399
• Main Authors: Nakabayashi, Hiromichi, Shimizu, Keiji
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; Angiogenesis; Animal models; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blotting, Western; Brain Neoplasms - blood supply; Brain Neoplasms - metabolism; Brain tumors; Cell culture; Cell Line, Tumor; Cell Movement - drug effects; Endothelial cells; Enzyme Activation - drug effects; Enzyme-Linked Immunosorbent Assay; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Gelatinase B; Gene Expression - drug effects; Glioma; Glioma - blood supply; Glioma - metabolism; Glioma cells; Humans; Invasiveness; MAP kinase; Matrix metalloproteinase; Medical sciences; Mitogen-Activated Protein Kinase Kinases - metabolism; Neovascularization, Pathologic - metabolism; Neurology; Phosphorylation; Polymerase chain reaction; Protein Kinase Inhibitors - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Rho-associated kinase; rho-Associated Kinases - metabolism; Signal Transduction - drug effects; Tumors; Tumors of the nervous system. Phacomatoses; Vascular endothelial growth factor; Western blotting
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2010.01794.x

Malignant gliomas are characterized by high invasive potential and strong angiogenic ability. Constitutive activation of Rho and its downstream target Rho‐kinase are crucial for tumor progression. We investigated the effect of the Rho‐kinase inhibitor HA1077 on tumor‐induced angiogenesis of malignant glioma cells and explored the molecular mechanisms underlying the effect of HA1077. Here, we demonstrated that HA1077 suppressed tube formation of endothelial cells in human umbilical vein endothelial cell (HUVEC)–glioma cell co‐culture assay. Western blot, RT‐PCR, ELISA and zymography demonstrated that HA1077 suppressed gene and protein expressions of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)‐2 and MMP‐9 in glioma cells. Furthermore, HA1077 attenuated the phosphorylation of extracellular signal‐regulated kinases 1 and 2 (ERK1/2) and the DNA binding activity of activator protein‐1, a key downstream transcriptional factor of ERK1/2. HA1077 also suppressed the migration of HUVEC in vitro. Thus, it is suggested that the anti‐angiogenic effect of HA1077 may be due to the combination of ROCK inhibition and mitogen‐activated protein kinase kinase (MEK)/ERK pathway inhibition. Moreover, an in vivo intracerebral human glioma cell xenograft mouse model demonstrated that HA1077 suppressed neovascularity and tumor growth. The results of the present study suggest that HA1077 has a therapeutic potential as an anti‐angiogenic agent against malignant gliomas. (Cancer Sci 2011; 102: 393–399)