Thrombospondin and apoptosis: molecular mechanisms and use for design of complementation treatments.
Thrombospondin-1 is the first and most studied naturally occurring protein inhibitor of angiogenesis. Its characteristic multi-domain structure determines thrombospondin-1 divergent functions, which include but are not limited to the regulation of angiogenesis. Below we overview the structural determinants and receptors expressed on the endothelial and other cell types, that are at the root of thrombospondin-1 striking ability to block neovascularization. We specifically emphasize thrombospondin-1 direct apoptotic action on the remodeling vascular endothelium and summarize current knowledge of its pro-apoptotic signaling and transcriptional networks. Further, we provide comprehensive survey of the thrombospondin-based anti-angiogenic strategies with special focus on the combination treatments. We convincingly illustrate how precise knowledge of the pro-apoptotic events and intermediates elicited by thrombospondin in the vascular endothelial cells facilitates the design of the most effective treatment combinations, where the efficacy of thrombospondin-derived compounds is maximized by the partner drug(s) ("complementation" strategies) and provide examples of such fine-tuning of the thrombospondin-based anti-angiogenic treatments.
Department of Urology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Tarry 16-703 Chicago, IL 60611-3008, USA.
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Mirochnik
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Kwiatek
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Volpert
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015195:Drug Design; D004359:Drug Therapy, Combination; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use; D019699:Thrombospondins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D019699:Thrombospondins