Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
Chem Biol Interact. 2015 May 5;232:58-67. doi: 10.1016/j.cbi.2015.03.008. Epub 2015 Mar 17.
Angiogenesis remain a critical procedure for tumor progression and malignancy. Anticancer agents targeting angiogenic cascades have been proved to be an effective strategy in the field of cancer therapeutics. The current study aims to explore the mechanistic prevention of angiogenesis and cancer cell proliferation by 1,1'-β-d-glucopyranosyl-3,3'-bis(5-bromoindolyl)-octyl methane (NGD16), a novel N-glycosylated derivative of 3,3'-diindolylmethane (DIM). NGD16 suppressed the viability of prostate cancer (PC-3), pancreatic adenocarcinoma (MiaPaca-2), colorectal cancer (COLO-205) and human umbilical vein endothelial cells (HUVECs) effectively with IC50 values 0.8 μM, 2.8 μM, 5.3 μM and 2.5 μM respectively. Abrogation of angiogenesis by NGD16 was promising in in vivo mouse Matrigel plug assay as well as in ex vivo sprouting of rat thoracic aorta. At the molecular level, NGD16 inhibited the expression of glucose regulated protein, 78 kDa (GRP78), vascular endothelial growth factor receptor-2 (VEGFR2) and matrix metalloproteinase-9 (MMP-9) expression, the main mediators of angiogenesis and neovessel formation. Overexpression of GRP78 upregulated the expression of MMP-9 and VEGFR2 in PC-3 and HUVECs. Antibody blocking of GRP78 further potentiated NGD16 in attenuating angiogenesis through inhibition of MMP-9. NGD16 depicted its promising biodistribution profile in a pharmacokinetic study with 46.9% intraperitoneal bioavailability. Our findings suggest NGD16 is a potent inhibitor of neo-angiogenesis with a desirable pharmacokinetic profile, which can be taken forward in its development as an anticancer drug.
血管生成仍然是肿瘤进展和恶性肿瘤的关键过程。靶向血管生成级联的抗癌药物已被证明是癌症治疗领域的一种有效策略。本研究旨在探索 1,1'-β-d-吡喃葡萄糖基-3,3'-双(5-溴吲哚基)-辛基甲烷 (NGD16) 通过抑制血管生成和癌细胞增殖的作用机制，NGD16 是 3,3'-二吲哚基甲烷 (DIM) 的新型 N-糖基化衍生物。NGD16 对前列腺癌 (PC-3)、胰腺腺癌 (MiaPaca-2)、结直肠癌 (COLO-205) 和人脐静脉内皮细胞 (HUVEC) 的活力具有显著的抑制作用，IC50 值分别为 0.8 μM、2.8 μM、5.3 μM 和 2.5 μM。NGD16 在体内小鼠 Matrigel plugs 实验和大鼠胸主动脉体外发芽实验中均能有效抑制血管生成。在分子水平上，NGD16 抑制葡萄糖调节蛋白 78kDa (GRP78)、血管内皮生长因子受体-2 (VEGFR2) 和基质金属蛋白酶-9 (MMP-9) 的表达，这些是血管生成和新血管形成的主要介质。在 PC-3 和 HUVECs 中，过表达 GRP78 上调了 MMP-9 和 VEGFR2 的表达。GRP78 抗体阻断进一步增强了 NGD16 通过抑制 MMP-9 减轻血管生成的作用。在药代动力学研究中，NGD16 的腹腔内生物利用度为 46.9%，显示出其有很好的生物分布特征。我们的研究结果表明，NGD16 是一种有前途的新型血管生成抑制剂，具有理想的药代动力学特征，可作为抗癌药物进一步开发。
