Control of Melanoma Invasiveness by Anticollagenolytic Agents: A Reappraisal of an Old Concept

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Editor-in-Chief:
Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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Control of Melanoma Invasiveness by Anticollagenolytic Agents: A Reappraisal of an Old Concept



Anti-Cancer Agents in Medicinal Chemistry, 9(5): 576-597.

Author(s): Erika Bourguet, Janos Sapi, Herve Emonard and William Hornebeck.

Affiliation: Universite de Reims Champagne- Ardenne, UMR 6237 CNRS, Faculte de Medecine, 51 rue Cognacq- Jay, 51095 Reims Cedex, France.

Abstract

Collagen, the major constituent of human dermis, represents the main barrier against progression of melanoma cells. Several matrix metalloproteinases (MMPs), i.e. collagenase-1 (MMP-1), gelatinase A (MMP-2) and membrane-type 1-MMP (MMP-14), favor melanoma cell invasion through their capacity of degrading collagen and thus, are considered as main targets. Potent inhibitors, as hydroxamate- derived pseudopeptides were first proposed as pharmacological agents to control melanoma invasiveness. These molecules have major drawbacks linked to i) toxicity and ii) absence of specificity, in keeping with the high Zn chelating property of hydroxamates, that might hinder the contribution of the occupancy of other subsites in enzyme inhibition. To date, research focuses on the design of compounds which display a lower affinity for Zn in enzyme active site. For instance, hydroxamate can be replaced by phosphinic acid or hydrazide which further allows synthesis of both right- and left- hand side inhibitors and therefore occupancy of non-primed enzyme subsites. Novel types of selective MMP inhibitors also include non-competitive and mechanism- based inhibitors. Finally, collagenolysis may be controlled by modulating enzyme-substrate interaction through the identification of substances that bind to MMP exosites. Such compounds could be of value by impeding collagenases to associate to plasma-membrane of invading cancer cells.

Keywords:

Melanoma, matrix metalloproteinases, collagenase, collagen, inhibitors, exosite.



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Article Details

Volume: 9
Issue Number: 5
First Page: 576
Last Page: 597
Page Count: 22
DOI: 10.2174/187152009788451842
Price: $58
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