Apicidin, an inhibitor of histone deacetylase, prevents H-ras-induced invasive phenotype.
Cancer metastasis represents the most important cause of cancer death and agents that may inhibit tumor cell invasion have been extensively pursued. In the present study, we have examined the anti-invasive effect of apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl -L-2-amin o-8-oxodecanoyl)], a fungal metabolite that was identified as an antiprotozoal agent known to inhibit parasite histone deacetylase (HDAC). We show that apicidin significantly inhibits H-ras-induced invasive phenotype of MCF10A human breast epithelial cells in parallel with a specific downregulation of matrix metalloproteinase (MMP)-2, but not MMP-9. We also show that apicidin induces a morphological reversal and growth inhibition of H-ras MCF10A cells similar to that induced by other HDAC inhibitors. Taken in conjunction with the fact that uncontrolled ras activation is probably the most common genetic defect in human cancer cells, our data showing the anti-invasive and detransforming activities of apicidin in H-ras-transformed MCF10A cells may suggest a potential use of HDAC inhibitors for treatment of cancer.
Kim
M S
MS
College of Pharmacy, Duksung Women's University, Seoul, South Korea.
Son
M W
MW
Kim
W B
WB
In Park
Y
Y
Moon
A
A
D001940:Breast / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011905:Genes, ras / Q000187:drug effects* / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010641:Phenotype
D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9