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
Department of Medicine, The Sackler Institute, University College London, United Kingdom.
Cancer Res. 2005 Sep 15;65(18):8339-49. doi: 10.1158/0008-5472.CAN-05-0121.
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.
本研究的目的是探究最近鉴定出的磷脂酰肌醇3激酶（PI3K）/Akt抑制剂肌醇（1,3,4,5,6）五磷酸酯[Ins(1,3,4,5,6)P5]的抗血管生成及体内特性。由于PI3K/Akt信号通路的激活是导致血管生成的某些事件中的关键步骤，因此在人脐静脉内皮细胞（HUVEC）中测试了Ins(1,3,4,5,6)P5对碱性成纤维细胞生长因子（FGF-2）诱导的Akt磷酸化、细胞存活、迁移及体外管腔形成的影响。使用皮下植入基质胶的小鼠模型评估了Ins(1,3,4,5,6)P5对FGF-2诱导的体内血管生成的影响。此外，还测试了Ins(1,3,4,5,6)P5对卵巢癌SKOV-3异种移植瘤生长的影响。在此，我们表明FGF-2可诱导HUVEC中的Akt磷酸化，从而对血清饥饿细胞产生抗凋亡作用并增加细胞迁移能力。Ins(1,3,4,5,6)P5可阻断FGF-2介导的Akt磷酸化，并抑制HUVEC中的存活和迁移。此外，Ins(1,3,4,5,6)P5可抑制接种于基质胶上的HUVEC的FGF-2介导的毛细血管管腔形成以及BALB/c小鼠中FGF-2诱导血管生成反应。最后，Ins(1,3,4,5,6)P5可在同等程度上阻断裸鼠体内SKOV-3异种移植瘤的皮下生长，且它在体内可完全抑制Akt磷酸化。这些数据明确地将Akt抑制剂Ins(1,3,4,5,6)P5鉴定为一种特异性抗血管生成和抗肿瘤因子。PI3K/Akt信号通路的不适当激活与包括癌症在内的多种疾病的发生有关，这使得该信号通路成为治疗策略的一个有吸引力的靶点。在这方面，Ins(1,3,4,5,6)P5是一种具有特定促凋亡和抗血管生成特性的水溶性天然化合物，可能会带来成功的抗癌治疗策略。
