Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase.
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.
Kim
Y B
YB
Department of Biotechnology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.
Lee
K H
KH
Sugita
K
K
Yoshida
M
M
Horinouchi
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000235:genetics; D016213:Cyclins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003587:Cytomegalovirus / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018260:Gelsolin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008322:Mammals; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics; D011518:Proto-Oncogene Proteins; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D018260:Gelsolin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011518:Proto-Oncogene Proteins; C100692:oxamflatin; D019938:Cyclin D1; C012589:trichostatin A; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases