Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Toxicol Appl Pharmacol. 2013 Nov 1;272(3):616-24. doi: 10.1016/j.taap.2013.07.014. Epub 2013 Aug 3.
Since the introduction of angiogenesis as a useful target for cancer therapy, few agents have been approved for clinical use due to the rapid development of resistance. This problem can be minimized by simultaneous targeting of multiple angiogenesis signaling pathways, a potential strategy in cancer management known as polypharmacology. The current study aimed at exploring the anti-angiogenic activity of OSU-A9, an indole-3-carbinol-derived pleotropic agent that targets mainly Akt-nuclear factor-kappa B (NF-κB) signaling which regulates many key players of angiogenesis such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Human umbilical vein endothelial cells (HUVECs) were used to study the in vitro anti-angiogenic effect of OSU-A9 on several key steps of angiogenesis. Results showed that OSU-A9 effectively inhibited cell proliferation and induced apoptosis and cell cycle arrest in HUVECs. Besides, OSU-A9 inhibited angiogenesis as evidenced by abrogation of migration/invasion and Matrigel tube formation in HUVECs and attenuation of the in vivo neovascularization in the chicken chorioallantoic membrane assay. Mechanistically, Western blot, RT-PCR and ELISA analyses showed the ability of OSU-A9 to inhibit MMP-2 production and VEGF expression induced by hypoxia or phorbol-12-myristyl-13-acetate. Furthermore, dual inhibition of Akt-NF-κB and mitogen-activated protein kinase (MAPK) signaling, the key regulators of angiogenesis, was observed. Together, the current study highlights evidences for the promising anti-angiogenic activity of OSU-A9, at least in part through the inhibition of Akt-NF-κB and MAPK signaling and their consequent inhibition of VEGF and MMP-2. These findings support OSU-A9's clinical promise as a component of anticancer therapy.
自从将血管生成作为癌症治疗的有用靶点引入以来，由于耐药性的迅速发展，仅有少数药物被批准用于临床应用。通过同时靶向多个血管生成信号通路，可以最小化这个问题，这种策略被称为多药理学，是癌症管理中的一种潜在策略。本研究旨在探索 OSU-A9 的抗血管生成活性，OSU-A9 是一种吲哚-3-甲醇衍生的多效性药物，主要靶向 Akt-核因子-κB（NF-κB）信号通路，该信号通路调节血管内皮生长因子（VEGF）和基质金属蛋白酶（MMPs）等许多血管生成的关键参与者。本研究使用人脐静脉内皮细胞（HUVEC）来研究 OSU-A9 在血管生成的几个关键步骤中的体外抗血管生成作用。结果表明，OSU-A9 可有效抑制 HUVEC 细胞增殖，并诱导细胞凋亡和细胞周期停滞。此外，OSU-A9 抑制血管生成，表现为抑制 HUVEC 细胞的迁移/侵袭和 Matrigel 管形成，并减弱鸡胚绒毛尿囊膜实验中的体内新生血管形成。机制上，Western blot、RT-PCR 和 ELISA 分析表明，OSU-A9 能够抑制缺氧或佛波醇 12-肉豆蔻酸 13-乙酸诱导的 MMP-2 产生和 VEGF 表达。此外，观察到 Akt-NF-κB 和丝裂原活化蛋白激酶（MAPK）信号通路的双重抑制，这是血管生成的关键调节剂。总之，本研究强调了 OSU-A9 具有有前途的抗血管生成活性的证据，至少部分通过抑制 Akt-NF-κB 和 MAPK 信号及其随后对 VEGF 和 MMP-2 的抑制。这些发现支持 OSU-A9 作为癌症治疗药物的一部分的临床前景。
