Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects
| Autor: | Albana Cumashi, Manuela Iezzi, Paolo Innocenti, Enza Piccolo, Adolfo Saiardi, Massimo Broggini, Barry V. L. Potter, Andrew M. Riley, Stefano Iacobelli, Marco Falasca, Cosmo Rossi, Tania Maffucci, H. Yasmin Godage |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Angiogenesis Inositol Phosphates Basic fibroblast growth factor Angiogenesis Inhibitors Antineoplastic Agents Cell Growth Processes chemistry.chemical_compound Mice Phosphatidylinositol 3-Kinases Cell Movement Cell Line Tumor Medicine Animals Humans Drug Interactions Phosphatidylinositol Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Cells Cultured Phosphoinositide-3 Kinase Inhibitors Ovarian Neoplasms Matrigel Mice Inbred BALB C Phosphoinositide 3-kinase biology business.industry Endothelial Cells Xenograft Model Antitumor Assays Inositol pentakisphosphate Drug Combinations Oncology chemistry Biochemistry biology.protein Cancer research Female Fibroblast Growth Factor 2 Proteoglycans Collagen Laminin business Proto-Oncogene Proteins c-akt |
| Zdroj: | Cancer research. 65(18) |
| ISSN: | 0008-5472 |
| Popis: | The purpose of this study was to investigate the antiangiogenic and in vivo properties of the recently identified phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor Inositol(1,3,4,5,6) pentakisphosphate [Ins(1,3,4,5,6)P5]. Because activation of the PI3K/Akt pathway is a crucial step in some of the events leading to angiogenesis, the effect of Ins(1,3,4,5,6)P5 on basic fibroblast growth factor (FGF-2)–induced Akt phosphorylation, cell survival, motility, and tubulogenesis in vitro was tested in human umbilical vein endothelial cells (HUVEC). The effect of Ins(1,3,4,5,6)P5 on FGF-2-induced angiogenesis in vivo was evaluated using s.c. implanted Matrigel in mice. In addition, the effect of Ins(1,3,4,5,6)P5 on growth of ovarian carcinoma SKOV-3 xenograft was tested. Here, we show that FGF-2 induces Akt phosphorylation in HUVEC resulting in antiapoptotic effect in serum-deprived cells and increase in cellular motility. Ins(1,3,4,5,6)P5 blocks FGF-2-mediated Akt phosphorylation and inhibits both survival and migration in HUVEC. Moreover, Ins(1,3,4,5,6)P5 inhibits the FGF-2-mediated capillary tube formation of HUVEC plated on Matrigel and the FGF-2-induced angiogenic reaction in BALB/c mice. Finally, Ins(1,3,4,5,6)P5 blocks the s.c. growth of SKOV-3 xenografted in nude mice to the same extent than cisplatin and it completely inhibits Akt phosphorylation in vivo. These data definitively identify the Akt inhibitor Ins(1,3,4,5,6)P5 as a specific antiangiogenic and antitumor factor. Inappropriate activation of the PI3K/Akt pathway has been linked to the development of several diseases, including cancer, making this pathway an attractive target for therapeutic strategies. In this respect, Ins(1,3,4,5,6)P5, a water-soluble, natural compound with specific proapoptotic and antiangiogenic properties, might result in successful anticancer therapeutic strategies. |
| Databáze: | OpenAIRE |
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