Biochemical Pharmacology 2012-11-01

Novel mithramycins abrogate the involvement of protein factors in the transcription of cell cycle control genes.

Carolina Vizcaíno, Sylvia Mansilla, Luz-Elena Núñez, Carmen Méndez, José A Salas, Francisco Morís, José Portugal

Index: Biochem. Pharmacol. 84(9) , 1133-42, (2012)

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Abstract

The effects of mithramycin SK (MSK) and demycarosyl-3D-β-D-digitoxosyl-mithramycin SK (DIG-MSK; EC-8042), two novel analogs of the antitumor antibiotic mithramycin A, on gene transcription were examined in human HCT116 colon carcinoma cells by quantitative real-time PCR of 89 genes mainly involved in cell cycle control. Each one of the analogs down-regulated a different set of genes, while only five genes were down-regulated by both compounds. Moreover, other genes were significantly up-regulated, among them p21(WAF1)/CDKN1A which is involved in halting cells at the G1 and G2/M checkpoints. These results are rationalized in terms of MSK or DIG-MSK competition with various transcription factors for binding to consensus C/G-rich tracts encompassed in gene promoters. Changes in cell cycle distribution and protein levels after treatment with every analog were consistent with changes observed in gene expression.Copyright © 2012 Elsevier Inc. All rights reserved.