Document Detail

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase.
MedLine Citation:
PMID:  10229197     Owner:  NLM     Status:  MEDLINE    
Oxamflatin [(2E)-5-[3-[(phenylsufonyl) aminol phenyl]-pent-2-en-4-ynohydroxamic acid] induces transcriptional activation of junD and morphological reversion in various NIH3T3-derived transformed cell lines. We found that oxamflatin showed in vitro antiproliferative activity against various mouse and human tumor cell lines with drastic changes in the cell morphology and in vivo antitumor activity against B16 melanoma. Oxamflatin caused an elongated cell shape with filamentous protrusions as well as arrest of the cell cycle at the G1 phase in HeLa cells. These phenotypic changes of HeLa cells were apparently similar to those by trichostatin A (TSA), a specific inhibitor of histone deacetylase (HDAC). The effect of oxamflatin on the transcriptional activity of the cytomegalovirus (CMV) promoter was examined and compared with known HDAC inhibitors, TSA, sodium n-butyrate, and FR901228. Oxamflatin as well as all these inhibitors greatly enhanced the transcriptional activity of the CMV promoter in a dose-dependent manner. Oxamflatin, like TSA, inhibited intracellular HDAC activity, as a result of which marked amounts of acetylated histone species accumulated. Finally, effects on expression of several endogenous genes involved in cell morphology and cell cycle control in HeLa cells were analysed. Expression of gelsolin, cyclin E and Cdk inhibitors including p21WAF1/Cip1 was highly augmented, while that of cyclin A and cyclin D1 was decreased by oxamflatin. These results suggest that changes in the expression pattern of the genes regulating cell morphology and the cell cycle due to histone hyperacetylation are responsible for the antitumor activity, the morphological change and the cell cycle arrest induced by oxamflatin.
Y B Kim; K H Lee; K Sugita; M Yoshida; S Horinouchi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncogene     Volume:  18     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  1999 Apr 
Date Detail:
Created Date:  1999-05-19     Completed Date:  1999-05-19     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  2461-70     Citation Subset:  IM    
Department of Biotechnology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.
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MeSH Terms
Antineoplastic Agents / pharmacology*
CDC2-CDC28 Kinases*
Cell Division / drug effects
Cyclin A / drug effects,  genetics,  metabolism
Cyclin D1 / drug effects,  genetics,  metabolism
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases / drug effects,  genetics
Cyclins / drug effects,  genetics,  metabolism
Cytomegalovirus / drug effects,  genetics
Drug Screening Assays, Antitumor
Enzyme Inhibitors / pharmacology
Gelsolin / drug effects,  genetics,  metabolism
Gene Expression Regulation / drug effects
HeLa Cells / cytology,  drug effects
Histone Deacetylase Inhibitors*
Hydroxamic Acids / pharmacology*
Melanoma, Experimental / drug therapy
Peritoneal Neoplasms / drug therapy
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases / drug effects,  genetics
Proto-Oncogene Proteins*
Reg. No./Substance:
0/Antineoplastic Agents; 0/CDKN1A protein, human; 0/Cdkn1a protein, mouse; 0/Cyclin A; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Enzyme Inhibitors; 0/Gelsolin; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Proto-Oncogene Proteins; 0/oxamflatin; 136601-57-5/Cyclin D1; 58880-19-6/trichostatin A; EC Kinases; EC Kinases; EC protein, human; EC protein, human; EC protein, mouse; EC protein, mouse; EC Kinase 2; EC Kinase 4; EC Kinases

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