Structure-activity relationship of 17 structural analogues of n-butyric acid upon c-myc expression.
Terminal differentiation of hematopoietic cells in vivo and in vitro is almost invariably accompanied by down-regulated expression of the c-myc proto-oncogene. Constitutive expression of c-myc in tumor cells inhibits terminal differentiation and maintains proliferation. In Burkitt's lymphoma, chromosomal translocations cause a deregulation of the c-myc gene through fusion of this locus with one of the immunoglobulin gene loci. However, the down-regulation of c-myc by n-butyric acid, a potent inducer of differentiation, is also observed in BL cells. Unlike other inducers of differentiation such as dimethylsulfoxide or hexamethylenebisacetamide, which down-regulate c-myc expression, albeit transiently, n-butyric acid causes a continuous, transcriptional shut-off. Because of the possible therapeutic implication of this finding, we have assayed structural analogues of n-butyric acid for their effect on c-myc expression in Burkitt's lymphoma cells. Of the analogues tested, 12 were active and 5 were inactive. Only unbranched fatty acids with 4 and 5 carbon atoms showed activity, a 4-carbon chain being optimal. 3-chloropropionic acid had maximal activity at a 3-fold lower concentration than n-butyric acid (1 mM versus 3 mM). The corresponding ester-analogues were equally effective. Those analogues found capable of down-regulating c-myc in Burkitt's lymphoma cells were similarly effective in their ability to induce terminal differentiation in murine erythroleukemia cells.
Rottleb
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Institut für Medizinische Mikrobiologie, Universität Regensburg, Germany.
Hall
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Bornkamm
G W
GW
Polack
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A
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology; D002087:Butyrates / Q000737:chemistry* / Q000494:pharmacology*; D020148:Butyric Acid; D002454:Cell Differentiation / Q000187:drug effects; D005227:Fatty Acids / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc / Q000235:genetics*; D051379:Mice; D015394:Molecular Structure; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002087:Butyrates; D005227:Fatty Acids; D011422:Propionates; D012333:RNA, Messenger; D020148:Butyric Acid; C007022:3-chloropropionic acid