Asiatic acid inhibits pro-angiogenic effects of VEGF and human gliomas in endothelial cell culture models.
Asiatic acid inhibits pro-angiogenic effects of VEGF and human gliomas in endothelial cell culture models.
复制标题
DOI：
10.1371/journal.pone.0022745
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Deep G
中科院分区：
文献类型：
--
作者：
Kavitha CV;Agarwal C;Agarwal R;Deep G
恶性神经胶质瘤是最具破坏性和无法治愈的肿瘤之一。神经胶质瘤细胞持续过度的血管生成是其不受控制的生长和对传统疗法产生耐药性并导致高死亡率的主要原因。因此，靶向血管生成应该是预防或控制神经胶质瘤细胞生长的合理策略。早期研究表明积雪草酸（AsA）是一种五环三萜类化合物，可有效对抗神经胶质瘤和其他癌细胞；然而，其对抗血管生成的功效仍然未知。在本研究中，我们使用人脐静脉内皮细胞 (HUVEC) 和人脑微血管内皮细胞 (HBMEC) 检测了 AsA 的抗血管生成功效。我们的结果表明，AsA (5–20 µM) 通过激活半胱天冬酶（3 和 9）并调节细胞凋亡调节因子 Bad、survivin 和 pAkt-ser473 的表达来抑制 HUVEC 生长并诱导细胞凋亡。此外，AsA 显示出对 HUVEC 迁移、侵袭和毛细管形成的剂量依赖性抑制，并破坏预先形成的毛细血管网络。 AsA 还抑制 HUVEC 和 HBMEC 的 VEGF 刺激的生长和毛细管形成。接下来，我们分析了从用 DMSO（对照条件培养基，CCM）或 AsA 20 µM（AsA20 条件培养基，AsA20CM）处理的人胶质瘤 LN18 和 U87-MG 细胞中收集的条件培养基的血管生成潜力。来自神经胶质瘤细胞的 CCM 显着增强了 HUVEC 和 HBMEC 中的毛细管形成，而两种内皮细胞系中的毛细管形成在 AsA20CM 的存在下大大受损。与这些结果一致，与 CCM 相比，AsA20CM 中的 VEGF 表达较低，并且实际上 AsA 强烈抑制神经胶质瘤细胞中的 VEGF 水平（细胞和分泌的）。 AsA还在Matrigel栓塞试验中显示出剂量依赖性的抗血管生成功效，并抑制神经胶质瘤细胞吸引HUVEC/HBMEC的潜力。总体而言，本研究清楚地表明了 AsA 强大的抗血管生成潜力，并表明其可用于对抗恶性神经胶质瘤。
Malignant gliomas are one of the most devastating and incurable tumors. Sustained excessive angiogenesis by glioma cells is the major reason for their uncontrolled growth and resistance toward conventional therapies resulting in high mortality. Therefore, targeting angiogenesis should be a logical strategy to prevent or control glioma cell growth. Earlier studies have shown that Asiatic Acid (AsA), a pentacyclic triterpenoid, is effective against glioma and other cancer cells; however, its efficacy against angiogenesis remains unknown. In the present study, we examined the anti-angiogenic efficacy of AsA using human umbilical vein endothelial cells (HUVEC) and human brain microvascular endothelial cells (HBMEC). Our results showed that AsA (5–20 µM) inhibits HUVEC growth and induces apoptotic cell death by activating caspases (3 and 9) and modulating the expression of apoptosis regulators Bad, survivin and pAkt-ser473. Further, AsA showed a dose-dependent inhibition of HUVEC migration, invasion and capillary tube formation, and disintegrated preformed capillary network. AsA also inhibited the VEGF-stimulated growth and capillary tube formation by HUVEC and HBMEC. Next, we analyzed the angiogenic potential of conditioned media collected from human glioma LN18 and U87-MG cells treated with either DMSO (control conditioned media, CCM) or AsA 20 µM (AsA20 conditioned media, AsA20CM). CCM from glioma cells significantly enhanced the capillary tube formation in both HUVEC and HBMEC, while capillary tube formation in both endothelial cell lines was greatly compromised in the presence of AsA20CM. Consistent with these results, VEGF expression was lesser in AsA20CM compared to CCM, and indeed AsA strongly inhibited VEGF level (both cellular and secreted) in glioma cells. AsA also showed dose-dependent anti-angiogenic efficacy in Matrigel plug assay, and inhibited the glioma cells potential to attract HUVEC/HBMEC. Overall, the present study clearly showed the strong anti-angiogenic potential of AsA and suggests its usefulness against malignant gliomas.
登录
查看更多内容
影响因子：
0.7
作者：
Bunpo, Piyawan;Kataoka, Keiko;Ohnishi, Yoshinari
通讯作者：
Ohnishi, Yoshinari
影响因子：
3.4
作者：
Gu, QY;Wang, DW;Deng, H
通讯作者：
Deng, H
影响因子：
8
作者：
Agarwal, C;Singh, RP;Agarwal, R
通讯作者：
Agarwal, R
影响因子：
4.8
作者：
Gingis-Velitski, S;Zetser, A;Ilan, N
通讯作者：
Ilan, N
影响因子：
158.5
作者：
Hurwitz, H;Fehrenbacher, L;Kabbinavar, F
通讯作者：
Kabbinavar, F