Analysis of the effects of daunorubicin and WP631 on transcription

The proficiency with which anthracyclines and other DNA-binding drugs targe t certain sequences in eukaryotic promoters offers a potential approach to interfere with the mechanisms that regulate gene expression in tumor cells. An in vitro transcription assay has been used to compare the ability of th e bisintercalating anthracycline WP631 and the monointercalating anthracycl ine daunorubicin in terms of their ability to inhibit initiation of transcr iption of the adenovirus major late promoter linked to a G-less transcribed DNA template. Both drugs inhibit basal transcription by RNA polymerase II. However, WP631 is similar to 15 times more efficient at inhibiting transcr iption initiation from an adenovirus promoter containing an upstream Spl-pr otein binding site. The differences in the ability of each drug to inhibit transcription initiation appear to be related to the competition between Sp l and the anthracyclines for binding to the same site. To see whether WP631 's strong effect on transcription can also be observed in cells, we compare d the effects of WP631 and other anthracyclines on the transcription of the c-myc gene, which promoter contains Sp1 binding sites. The resulting data suggest that WP631 might circumvent some kinds of tumor resistance at rathe r low drug concentrations, inhibit c-myc expression in some cell lines, and exert its antitumoral effect by inducing apoptosis.