Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects

Tania Maffucci, Enza Piccolo, Albana Cumashi, Manuela Iezzi, Andrew M. Riley, Adolfo Saiardi, H. Yasmin Godage, Cosmo Rossi, Massimo Broggini, Stefano Iacobelli, Barry V L Potter, Paolo Innocenti, Marco Falasca

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

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) pentakisphospliate [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 antiapoptolic 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.

Original languageEnglish
Pages (from-to)8339-8349
Number of pages11
JournalCancer Research
Volume65
Issue number18
DOIs
Publication statusPublished - Sep 15 2005

Fingerprint

Phosphatidylinositol 3-Kinase
Fibroblast Growth Factor 2
Human Umbilical Vein Endothelial Cells
Phosphorylation
inositol-1,3,4,5,6-pentakisphosphate
inositol pentaphosphate
Angiogenesis Inducing Agents
Inositol
Growth
Heterografts
Nude Mice
Cisplatin
Cell Movement
Cell Survival
Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects. / Maffucci, Tania; Piccolo, Enza; Cumashi, Albana; Iezzi, Manuela; Riley, Andrew M.; Saiardi, Adolfo; Godage, H. Yasmin; Rossi, Cosmo; Broggini, Massimo; Iacobelli, Stefano; Potter, Barry V L; Innocenti, Paolo; Falasca, Marco.

In: Cancer Research, Vol. 65, No. 18, 15.09.2005, p. 8339-8349.

Research output: Contribution to journalArticle

Maffucci, T, Piccolo, E, Cumashi, A, Iezzi, M, Riley, AM, Saiardi, A, Godage, HY, Rossi, C, Broggini, M, Iacobelli, S, Potter, BVL, Innocenti, P & Falasca, M 2005, 'Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects', Cancer Research, vol. 65, no. 18, pp. 8339-8349. https://doi.org/10.1158/0008-5472.CAN-05-0121
Maffucci, Tania ; Piccolo, Enza ; Cumashi, Albana ; Iezzi, Manuela ; Riley, Andrew M. ; Saiardi, Adolfo ; Godage, H. Yasmin ; Rossi, Cosmo ; Broggini, Massimo ; Iacobelli, Stefano ; Potter, Barry V L ; Innocenti, Paolo ; Falasca, Marco. / Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects. In: Cancer Research. 2005 ; Vol. 65, No. 18. pp. 8339-8349.
@article{0e40f42a79184789b82ac17d45e634e4,
title = "Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects",
abstract = "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) pentakisphospliate [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 antiapoptolic 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.",
author = "Tania Maffucci and Enza Piccolo and Albana Cumashi and Manuela Iezzi and Riley, {Andrew M.} and Adolfo Saiardi and Godage, {H. Yasmin} and Cosmo Rossi and Massimo Broggini and Stefano Iacobelli and Potter, {Barry V L} and Paolo Innocenti and Marco Falasca",
year = "2005",
month = "9",
day = "15",
doi = "10.1158/0008-5472.CAN-05-0121",
language = "English",
volume = "65",
pages = "8339--8349",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects

AU - Maffucci, Tania

AU - Piccolo, Enza

AU - Cumashi, Albana

AU - Iezzi, Manuela

AU - Riley, Andrew M.

AU - Saiardi, Adolfo

AU - Godage, H. Yasmin

AU - Rossi, Cosmo

AU - Broggini, Massimo

AU - Iacobelli, Stefano

AU - Potter, Barry V L

AU - Innocenti, Paolo

AU - Falasca, Marco

PY - 2005/9/15

Y1 - 2005/9/15

N2 - 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) pentakisphospliate [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 antiapoptolic 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.

AB - 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) pentakisphospliate [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 antiapoptolic 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.

UR - http://www.scopus.com/inward/record.url?scp=24944582402&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24944582402&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-0121

DO - 10.1158/0008-5472.CAN-05-0121

M3 - Article

C2 - 16166311

AN - SCOPUS:24944582402

VL - 65

SP - 8339

EP - 8349

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 18

ER -