CMT-3, a non-antimicrobial tetracycline (TC), inhibits MT1-MMP activity: Relevance to cancer

Citation
Hm. Lee et al., CMT-3, a non-antimicrobial tetracycline (TC), inhibits MT1-MMP activity: Relevance to cancer, CURR MED CH, 8(3), 2001, pp. 257-260
Citations number
18
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Pharmacology & Toxicology
Journal title
CURRENT MEDICINAL CHEMISTRY
ISSN journal
0929-8673 → ACNP
Volume
8
Issue
3
Year of publication
2001
Pages
257 - 260
Database
ISI
SICI code
0929-8673(200102)8:3<257:CANT(I>2.0.ZU;2-B
Abstract
Tetracyclines (TCs) and their non-antimicrobial analogs (CMTs) have therape utic potential to inhibit tissue destructive disease processes, such as can cer invasion and metastasis, by inhibiting certain matrix metalloproteinase s. Enhanced matrix metalloproteinase-2 (MMP-2; gelatinase A) activity has b een correlated to cancer invasiveness, and membrane type MMP (MT1-MMP) expr essed by tumor cells is involved in localizing and activating pro-MMP-2, a pathway believed to mediate cancer induced tissue breakdown. CMT-3 (6-demet hyl, 6-deoxy, 4-dedimethylamino TC) has been shown to experimentally suppre ss prostate cancer, colon adenocarcinoma and melanoma invasiveness in cell culture and to inhibit tumor growth and metastasis in vivo and was used in the current in vitro study. Confluent MT1-MMP transfected COS-I cells were harvested, washed thoroughly, subjected to N-2 cavitation and cell membrane enriched fractions were isolated by sequential centrifugations. This MT1-M MP preparation exhibited (i) pro-MMP-2 activating activity as shown by mole cular weight shift of this gelatinase From 72 kDa to 62 kDa using gelatin z ymography, and (ii) the ability to degrade both [H-3-methyl] gelatin and ca sein at 37 degreesC. Adding CMT-3 at final concentrations of 5 - 20 muM inh ibited MT1-MMP gelatinolytic and caseinolytic activity, blocked MT1-MMP act ivation of pro-MMP-2, and decreased invasiveness (using the Matrigel system ) of HT-1080 fibrosarcoma cells. The inhibition of MT1-MMP by CMT-3 may par tially explain the inhibition of cancer cell -mediated tissue breakdown and invasiveness by this non-antimicrobial tetracycline analog.