Lu Cong-Xiao, Li Jing, Sun Yong-Xu, Qi Xin, Wang Qing-Juan, Xin Xian-Liang, Geng Mei-Yu
Department of Pharmacy, Yantai Yuhuangding Hospital, Yantai 264000, and Department of Molecular Pharmacology, Marine Drug and Food Institute, School of Medicine and Pharmacy, Ocean University of China, Qingdao, PR China.
Biochem Pharmacol. 2007 Nov 1;74(9):1330-9. doi: 10.1016/j.bcp.2007.06.012. Epub 2007 Jun 16.
Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors released from KS and host cells and HIV viral products-the protein Tat are reported to be involved in angiogenesis. Mounting evidence further suggests that multiple angiogenic activities of Tat contribute to AIDS-associated Kaposi's sarcoma (AIDS-KS). Herein, we report that sulfated polymannuroguluronate (SPMG), a novel anti-AIDS drug candidate now undergoing phase II clinical trial, significantly eliminated Tat-induced angiogenesis in SLK cells both in vitro and in vivo. SPMG significantly and dose-dependently inhibits proliferation, migration, and tube formation by SLK cells. SPMG also dramatically arrested Tat-driven KDR phosphorylation and blocked the interaction between Tat and integrin beta1, thus inhibiting the phosphorylation of the downstream kinases of FAK, paxillin and MAPKs. In addition, SPMG was noted to block the release of bFGF and VEGF from ECM. All these collectively favor an issue that SPMG functions as a promising therapeutic against Tat-induced angiogenesis and pathologic events relevant to AIDS-KS, which adds novel mechanistic profiling to the anti-AIDS action of SPMG.
卡波西肉瘤（KS）是一种常与医源性和获得性免疫抑制相关的肿瘤，其特征是显著的血管生成。据报道，KS和宿主细胞释放的血管生成因子以及HIV病毒产物——蛋白Tat参与了血管生成。越来越多的证据进一步表明，Tat的多种血管生成活性促成了与艾滋病相关的卡波西肉瘤（AIDS-KS）。在此，我们报告硫酸化聚甘露糖醛酸（SPMG），一种正在进行II期临床试验的新型抗艾滋病候选药物，在体外和体内均能显著消除Tat诱导的SLK细胞血管生成。SPMG显著且剂量依赖性地抑制SLK细胞的增殖、迁移和管腔形成。SPMG还显著阻止了Tat驱动的KDR磷酸化，并阻断了Tat与整合素β1之间的相互作用，从而抑制了FAK、桩蛋白和丝裂原活化蛋白激酶下游激酶的磷酸化。此外，还发现SPMG可阻断bFGF和VEGF从细胞外基质的释放。所有这些共同支持了一个观点，即SPMG作为一种有前景的治疗药物，可对抗Tat诱导的血管生成以及与AIDS-KS相关的病理事件，这为SPMG的抗艾滋病作用增添了新的机制分析。
