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.