Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor |
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| Authors: | Dexin Kong Mutsumi Okamura Hisashi Yoshimi Takao Yamori |
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| Institution: | 1. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo, Japan;2. Research Laboratory, Zenyaku Kogyo Co. Ltd., 33-7, Ohizumi-machi, Nerima-ku, Tokyo, Japan;1. Department of Nuclear Medicine, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China;2. College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China;3. Medical Isotopes Research Center, Peking University, China;1. Laboratório de Biologia de Gliomas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Trindade, CEP: 88040-900, Florianópolis, SC, Brazil;2. Laboratório de Neuroquímica-4, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Trindade, CEP: 88040-900, Florianópolis, SC, Brazil;3. Laboratório Estrutura e Atividade (LEAT), Departamento de Química, Universidade Federal de Santa Catarina, Campus Trindade, CEP: 88040-900, Florianópolis, SC, Brazil;4. Laboratório de Genética, Divisão de Análises Clinicas, Hospital Universitário, Universidade Federal de Santa Catarina, Campus Trindade, CEP: 88040-900, Florianópolis, SC, Brazil;1. A. E. Arbuzov Institute of Organic, Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences, 420088 Kazan, Russian Federation;2. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation;1. Khlopin Radium Institute, 2-i Murinskii pr. 28, St. Petersburg 194021, Russia;2. Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26, St. Petersburg 198504, Russia;3. Department of Crystallography, St. Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russia;3. From the Hematology-Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104;4. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,;5. the Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, Colorado 80030, and;6. the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-9001 |
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| Abstract: | Angiogenesis is known to be required for tumour growth and metastasis. Recent reports indicated that phosphatidylinositol 3-kinase (PI3K) promoted angiogenesis by inducing expressions of HIF-1α and vascular endothelial growth factor (VEGF). The present study aims to investigate the antiangiogenic effect of ZSTK474, a novel pan-PI3K inhibitor. ZSTK474 significantly inhibited tumour growth in the RXF-631L xenograft model. Immunohistochemical staining of the tumour tissue with anti-von Willebrand Factor antibody showed a significantly reduced number of microvessels in the ZSTK474-treated mice, suggesting the highly promising antiangiogenic activity in vivo. In human umbilical vein endothelial cells (HUVECs), submicromolar concentrations of ZSTK474 inhibited cell growth, blocked VEGF-induced cell migration and the tube formation, and thus revealed potent in vitro antiangiogenic activity. Furthermore, ZSTK474 inhibited phosphorylation of Akt at submicromolar concentrations. In RXF-631L cancer cells, on the other hand, ZSTK474 treatment inhibited the expression of HIF-1α and secretion of VEGF. Together, these results suggest that ZSTK474 has potent antiangiogenic activity, which could be attributed to dual-target inhibitory properties: inhibition of VEGF secretion by cancer cells and inhibition of PI3K in endothelial cells. |
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