Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
PLoS One. 2010 Sep 3;5(9):e12563. doi: 10.1371/journal.pone.0012563.
In a recent study, we demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to inhibit the function of the epidermal growth factor receptor (EGFR). Lovastatin attenuated ligand-induced receptor activation and downstream signaling through the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in a variety of tumor derived cell lines. The vascular endothelial growth factor receptor (VEGFR) and EGFR share similar activation, internalization and downstream signaling characteristics.
METHODOLOGY/PRINCIPAL FINDINGS: The VEGFRs, particularly VEGFR-2 (KDR, Flt-1), play important roles in regulating tumor angiogenesis by promoting endothelial cell proliferation, survival and migration. Certain tumors, such as malignant mesothelioma (MM), also express both the VEGF ligand and VEGFRs that act in an autocrine loop to directly stimulate tumor cell growth and survival. In this study, we have shown that lovastatin inhibits ligand-induced VEGFR-2 activation through inhibition of receptor internalization and also inhibits VEGF activation of AKT in human umbilical vein endothelial cells (HUVEC) and H28 MM cells employing immunofluorescence and Western blotting. Combinations of lovastatin and a VEGFR-2 inhibitor showed more robust AKT inhibition than either agent alone in the H28 MM cell line. Furthermore, combining 5 µM lovastatin treatment, a therapeutically relevant dose, with two different VEGFR-2 inhibitors in HUVEC and the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity as demonstrated by MTT cell viability and flow cytometric analyses.
CONCLUSIONS/SIGNIFICANCE: These results highlight a novel mechanism by which lovastatin can regulate VEGFR-2 function and a potential therapeutic approach for MM through combining statins with VEGFR-2 inhibitors.
在最近的一项研究中，我们证明了洛伐他汀（一种强效的甲羟戊酸合成抑制剂）能够抑制表皮生长因子受体（EGFR）的功能。洛伐他汀通过 PI3K/AKT 途径减弱配体诱导的受体激活和下游信号。将洛伐他汀与吉非替尼（一种强效的 EGFR 抑制剂）联合使用，可在多种肿瘤衍生细胞系中诱导协同细胞毒性。血管内皮生长因子受体（VEGFR）与 EGFR 具有相似的激活、内化和下游信号特征。
方法/主要发现：VEGFRs，特别是 VEGFR-2（KDR、Flt-1），通过促进内皮细胞增殖、存活和迁移，在调节肿瘤血管生成中发挥重要作用。某些肿瘤，如恶性间皮瘤（MM），也表达 VEGF 配体和 VEGFRs，它们通过自分泌环直接刺激肿瘤细胞生长和存活。在这项研究中，我们已经表明，洛伐他汀通过抑制受体内化来抑制配体诱导的 VEGFR-2 激活，并且还通过免疫荧光和 Western blot 抑制 VEGF 激活 AKT 在人脐静脉内皮细胞（HUVEC）和 H28 MM 细胞中。洛伐他汀与 VEGFR-2 抑制剂的组合在 H28 MM 细胞系中比单独使用任何一种药物更能强烈抑制 AKT。此外，在 HUVEC 以及 H28 和 H2052 间皮瘤衍生细胞系中，将 5µM 洛伐他汀治疗（一种治疗相关剂量）与两种不同的 VEGFR-2 抑制剂联合使用，通过 MTT 细胞活力和流式细胞术分析证明了协同细胞毒性。
结论/意义：这些结果突出了洛伐他汀调节 VEGFR-2 功能的一种新机制，以及通过将他汀类药物与 VEGFR-2 抑制剂联合使用治疗 MM 的潜在治疗方法。
