Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-HIV Agents / administration & dosage
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Anti-HIV Agents / pharmacology*
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Anti-HIV Agents / therapeutic use
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Cell Adhesion / drug effects
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Collagen
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Combinations
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Escherichia coli / genetics
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Fibroblast Growth Factor 2 / metabolism
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Gene Products, tat / biosynthesis
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Gene Products, tat / pharmacology*
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Glutathione Transferase / metabolism
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HIV-1 / metabolism*
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Humans
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Laminin
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Male
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Mice
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Neovascularization, Pathologic / drug therapy*
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Neovascularization, Pathologic / metabolism
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Polysaccharides / administration & dosage
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Polysaccharides / pharmacology*
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Polysaccharides / therapeutic use
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Proteoglycans
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / pharmacology*
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Sarcoma, Kaposi* / blood supply
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Sarcoma, Kaposi* / metabolism
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Sarcoma, Kaposi* / pathology
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Anti-HIV Agents
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Drug Combinations
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Gene Products, tat
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Laminin
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Polysaccharides
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Proteoglycans
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Recombinant Fusion Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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sulfated polymannuroguluronate
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Fibroblast Growth Factor 2
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matrigel
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Collagen
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Glutathione Transferase