Abstract:
BACKGROUND AND PURPOSE:The use of tubulin-binding compounds, which act in part by inhibiting tumour angiogenesis, has become an integral strategy of tumour therapy. Recently, tubulysins were identified as a novel class of natural compounds of myxobacterial origin, which inhibit tubulin polymerization. As these compounds are structurally highly complex, the search for simplified precursors [e.g. pretubulysin (Prt)] and their derivatives is mandatory to overcome supply problems hampering clinical development. We tested the anti-angiogenic efficacy of Prt and seven of its derivatives in comparison to tubulysin A (TubA). EXPERIMENTAL APPROACH:The compounds were tested in cellular angiogenesis assays (proliferation, cytotoxicity, cell cycle, migration, chemotaxis, tube formation) and in vitro (tubulin polymerization). The efficacy of Prt was also tested in vivo in a murine subcutaneous tumour model induced with HUH7 cells; tumour size and vascularization were measured. KEY RESULTS:The anti-angiogenic potency of all the compounds tested ran parallel to their inhibition of tubulin polymerization in vitro. Prt showed nearly the same efficacy as TubA (EC(50) in low nanomolar range in all cellular assays). Some modifications in the Prt molecule caused only a moderate drop in potency, while others resulted in a dramatic loss of action, providing initial insight into structure-activity relations. In vivo, Prt completely prevented tumour growth and reduced vascular density to 30%. CONCLUSIONS AND IMPLICATIONS:Prt, a chemically accessible precursor of some tubulysins is a highly attractive anti-angiogenic compound both in vitro and in vivo. Even more simplified derivatives of this compound still retain high anti-angiogenic efficacy.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Rath S,Liebl J,Fürst R,Ullrich A,Burkhart JL,Kazmaier U,Herrmann J,Müller R,Günther M,Schreiner L,Wagner E,Vollmar AM,Zahler Sdoi
10.1111/j.1476-5381.2012.02037.xsubject
Has Abstractpub_date
2012-11-01 00:00:00pages
1048-61issue
5eissn
0007-1188issn
1476-5381journal_volume
167pub_type
杂志文章abstract::1. This study was undertaken to evaluate in vivo the influence of amiodarone on the effects of triiodothyronine (T3) in brown adipose tissue (BAT) which are independent of thyroid hormone synthesis and of the conversion of thyroxine (T4) to T3. Thyroidectomized rats were given a replacement dose of T3 (0.5 mg kg(-1) p...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702456
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journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1986.tb10172.x
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journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1991.tb09837.x
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journal_title:British journal of pharmacology
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