The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures
The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures
复制标题
DOI：
10.1158/1535-7163.mct-06-0698
复制
发表时间：
2007-09-01
影响因子：
5.7
通讯作者：
Abraham, Robert T.
中科院分区：
文献类型：
--
作者：
Howes, Amy L.;Chiang, Gary G.;Abraham, Robert T.
磷脂酰肌醇3-激酶（PI 3 K）通路在许多人类肿瘤中被激活，并介导细胞增殖、存活、粘附和运动等过程。天然产物渥曼青霉素已被广泛用于研究培养物中正常和转化细胞中PI 3 K抑制的功能后果，但由于稳定性和毒性问题而不是合适的癌症化疗剂。PX-866是一种改进的渥曼青霉素类似物，在异种移植模型中显示出显著的抗肿瘤活性。在这里，我们直接比较PX-866和渥曼青霉素在单层或三维球体培养的人癌细胞系。两种PI 3 K抑制剂在浓度高达100 nmol/L时均未能抑制单层细胞生长，但在低纳摩尔浓度时强烈抑制球状体生长，PX-866显示出比渥曼青霉素更大的效力。相对于渥曼青霉素，PX-866处理导致Akt磷酸化的更持续的损失，表明PX-866的增加的效力与PI 3 K信号传导的更持久的抑制有关。PX-866和渥曼青霉素都抑制球状体生长而不引起细胞毒性，类似于已知的细胞生长抑制剂，如雷帕霉素。PX-866在亚纳摩尔浓度下也抑制癌细胞运动。这些发现表明PX-866的抗肿瘤活性源于对PI 3 K通路的长期抑制和对细胞运动的抑制。此外，我们提出使用三维肿瘤模型更能预测PI 3 K抑制剂在缺乏磷酸酶和张力蛋白同源物活性或表达的癌细胞系中的体内生长抑制。
The phosphatidylinositol 3-kinase (PI3K) pathway is activated in many human tumors and mediates processes such as cell proliferation, survival, adhesion, and motility. The natural product, wortmannin, has been widely used to study the functional consequences of PI3K inhibition in both normal and transformed cells in culture but is not a suitable cancer chemotherapeutic agent due to stability and toxicity issues. PX-866, an improved wortmannin analogue, displays significant antitumor activity in xenograft models. Here, we directly compare PX-866 and wortmannin in human cancer cell lines cultured in monolayer or as three-dimensional spheroids. Both PI3K inhibitors failed to inhibit monolayer cell growth at concentrations up to 100 nmol/L but strongly suppressed spheroid growth at low nanomolar concentrations, with PX-866 showing greater potency than wortmannin. Relative to wortmannin, PX-866 treatment results in a more sustained loss of Akt phosphorylation, suggesting that the increased potency of PX-866 is related to a more durable inhibition of PI3K signaling. PX-866 and wortmannin both inhibit spheroid growth without causing cytotoxicity, similar to known cytostatic agents, such as rapamycin. PX-866 also inhibits cancer cell motility at subnanomolar concentrations. These findings suggest that the antitumor activities of PX-866 stem from prolonged inhibition of the PI3K pathway and inhibition of cell motility. In addition, we propose that the use of three-dimensional tumor models is more predictive of in vivo growth inhibition by PI3K inhibitors in cancer cell lines lacking phosphatase and tensin homologue activity or expression.