Analysis of the effects of daunorubicin and WP631 on transcription.
The proficiency with which anthracyclines and other DNA-binding drugs target 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 the bisintercalating anthracycline WP631 and the monointercalating anthracycline daunorubicin in terms of their ability to inhibit initiation of transcription 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 approximately 15 times more efficient at inhibiting transcription initiation from an adenovirus promoter containing an upstream Sp1-protein binding site. The differences in the ability of each drug to inhibit transcription initiation appear to be related to the competition between Sp1 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 compared 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 rather low drug concentrations, inhibit c-myc expression in some cell lines, and exert its antitumoral effect by inducing apoptosis.
Portugal
J
J
Departamento de Biología Molecular y Celular, Instituto de Biología Molecular de Barcelona, CSIC, Jordi Girona, 18-26, Barcelona, 08034, Spain. jpmbmc@cid.csic.es
Martín
B
B
Vaquero
A
A
Ferrer
N
N
Villamarín
S
S
Priebe
W
W
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D008969:Molecular Sequence Data; D014158:Transcription, Genetic / Q000187:drug effects*
D000903:Antibiotics, Antineoplastic; D007364:Intercalating Agents; C104426:WP 631; D003630:Daunorubicin