Ecteinascidin-743 inhibits activated but not constitutive transcription

Abstract

Ecteinascidin-743 (ET-743) is a promising chemotherapeutic agent currently in Phase III clinical trials. Previous studies indicated a novel spectrum of activity for this agent, including transcriptional inhibition. Initially hypothesized to target a single transcription factor (NF-Y), we now show that ET-743 is a more general inhibitor of activated transcription. Induction of the Sp1-regulated p21 gene by Trichostatin A (TSA) was blocked by ET-743 at concentrations that had minimal effect on uninduced (constitutive) expression. Moreover, ET-743 blocked induction of Gal4 fusion proteins by TSA without affecting activation mediated by the fusion proteins in the absence of the inducer. Finally, microarray analysis of SW620 cells treated with TSA and/or ET-743 indicated that activation of TSA-responsive promoters was blocked by ET-743 with little affect on nonresponsive promoters. These results, taken together with previous reports, leads us to suggest a mechanism whereby ET-743 is a novel, potent, and general inhibitor of activated but not uninduced transcription.