European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-09-18 , DOI: 10.1016/j.ejmech.2020.112851 Siddharth J. Modi , Vithal M. Kulkarni
Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis, which is an augmented production of proangiogenic factors by the tumor and its adjacent infected cells. These dysregulated angiogenic factors are the therapeutic targets in anti-angiogenic drug development. The signaling pathway of vascular endothelial growth factor (VEGF)/VEGFR-2 is crucial for controlling the angiogenic responses in endothelial cells (ECs). In this study, we carried out a rational drug design approach wherein we have identified the novel orally bioavailable compound VS 8 as a potent VEGFR-2 inhibitor, which remarkably suppresses hVEGF and hVEGFR-2 expression in HUVECs and exhibits significant anti-angiogenic effects in CAM assay. Besides, VS 8 significantly induces apoptosis in HCC cell line (Hep G2). Later we examined its effectiveness against CD44+ and CD133+ CSCs. Here, VS 8 was found to be active against CSCs, and adequate for the cessation of the cell cycle at ‘G0/G1’ and ‘S’ phase in CD44+ and CD133+ CSCs respectively. Factually, transforming growth factor-β (TGF-β) stimulated epithelial-mesenchymal transition (EMT) induces invasion and migration of HCC cells, which results in the metastasis. Therefore, we studied the effect of VS 8 on EMT markers using flow cytometry, which suggested that VS 8 significantly upregulates E-cadherin (epithelial biomarker) and downregulates vimentin (mesenchymal biomarker). Further, VS 8 downregulates the expression of EMT-inducing transcription factors (EMT-TFs), i.e., SNAIL. Altogether, our findings indicate that VS 8 could be a promising drug candidate for cancer therapy.
中文翻译:
发现具有对CD44 +和CD133 +癌症干细胞(CSCs)具有显着抗癌活性的VEGFR-2抑制剂:肝细胞癌中TGF-β诱导的上皮-间质转化(EMT)的逆转
肝细胞癌(HCC)是一种以新血管生成为特征的恶性肿瘤,其是肿瘤及其邻近感染细胞增加的促血管生成因子的产生。这些失调的血管生成因子是抗血管生成药物开发中的治疗靶标。血管内皮生长因子(VEGF)/ VEGFR-2的信号通路对于控制内皮细胞(EC)中的血管生成反应至关重要。在这项研究中,我们进行了合理的药物设计方法,其中我们已经确定了新型的口服生物利用化合物VS 8是有效的VEGFR-2抑制剂,它可以显着抑制HUVEC中的hVEGF和hVEGFR-2表达,并在HUVEC中表现出显着的抗血管生成作用CAM分析。此外,VS 8显着诱导HCC细胞系(Hep G2)的凋亡。后来我们检查了它对CD44 +和CD133 + CSC的有效性。在这里,VS 8被发现对CSC具有活性,并且足以终止CD44 +和CD133 + CSC中'G 0 / G 1 '和'S'期的细胞周期。实际上,转化生长因子-β(TGF-β)刺激的上皮-间质转化(EMT)诱导了HCC细胞的侵袭和迁移,从而导致了转移。因此,我们使用流式细胞术研究了VS 8对EMT标记的影响,这表明VS 8显着上调E-钙黏着蛋白(上皮生物标记)而下调波形蛋白(间质生物标记)。此外,VS 8下调EMT诱导转录因子(EMT-TFs)即SNAIL的表达。总而言之,我们的发现表明VS 8可能是有前途的癌症治疗药物。