Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, 411038, Maharashtra, India.
Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, 411038, Maharashtra, India.
Eur J Med Chem. 2020 Dec 1;207:112851. doi: 10.1016/j.ejmech.2020.112851. Epub 2020 Sep 18.
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 'G/G' 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.
肝细胞癌（HCC）是一种以新生血管形成为特征的恶性肿瘤，这是肿瘤及其相邻感染细胞产生促血管生成因子的增强。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点。血管内皮生长因子（VEGF）/VEGFR-2 信号通路对于控制内皮细胞（ECs）的血管生成反应至关重要。在这项研究中，我们采用了一种合理的药物设计方法，确定了新型口服生物可利用化合物 VS 8 是一种有效的 VEGFR-2 抑制剂，可显著抑制 HUVECs 中的 hVEGF 和 hVEGFR-2 表达，并在 CAM 测定中显示出显著的抗血管生成作用。此外，VS 8 可显著诱导肝癌细胞系（Hep G2）凋亡。随后，我们研究了其对 CD44+和 CD133+CSC 的有效性。结果表明，VS 8 对 CSC 有效，可分别使 CD44+和 CD133+CSC 的细胞周期停滞在“G/G”和“S”期。事实上，转化生长因子-β（TGF-β）刺激上皮-间充质转化（EMT）诱导 HCC 细胞侵袭和迁移，从而导致转移。因此，我们使用流式细胞术研究了 VS 8 对 EMT 标志物的影响，结果表明 VS 8 可显著上调 E-钙黏蛋白（上皮标志物），下调波形蛋白（间充质标志物）。此外，VS 8 下调 EMT 诱导转录因子（EMT-TFs）的表达，即 SNAIL。总之，我们的研究结果表明，VS 8 可能是一种有前途的癌症治疗药物候选物。
