Evidence for distinct regulation processes in the aclacinomycin- and doxorubicin-mediated differentiation of human erythroleukemic cells

Biochem Pharmacol. 1996 Mar 22;51(6):839-45. doi: 10.1016/0006-2952(95)02240-6.

Abstract

Human erythroleukemic K 562 cells were induced to were induced to differentiate along the erythroid lineage by anthracycline antitumor drugs, such as aclacinomycin (ACLA) and doxorubicin (DOX). Subsequent stimulation of heme and globin synthesis led to a differential quantitative expression of hemoglobins. Gower 1 (epsilon2, zeta2) was the major type for ACLA and X (epsilon2, gamma2) for DOX. Although ACLA and DOX increased both the expression of gamma-globin and porphobilinogen deaminase mRNAs, striking differences were observed in the expression of erythropoietin receptor mRNAs and in erythroid transcription factors GATA-1 and NF-E2, known to play a key role in erythroid gene regulation. Indeed, ACLA induces an increase either in the binding capacity of GATA-1 and NF-E2 or in the accumulation of erythropoietin receptor, GATA-1 and NF-E2 transcripts. In contrast, their expression with DOX was not significantly modified compared to uninduced cells, except for a slight decrease in NF-E2 expression on day 3. In conclusion, these data show that: 1. increased expression of erythroid transcription factors and erythroid genes are associated only with ACLA treatment, and 2. although cytotoxicity of both ACLA and DOX is certainly dependent on DNA intercalation, regulation of differentiation processes by these two drugs involves distinct mechanisms.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aclarubicin / analogs & derivatives*
  • Aclarubicin / pharmacology
  • Antibiotics, Antineoplastic / pharmacology*
  • Base Sequence
  • Cell Differentiation / drug effects
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Doxorubicin / pharmacology*
  • Erythroid-Specific DNA-Binding Factors
  • GATA1 Transcription Factor
  • Gene Expression / drug effects
  • Globins / biosynthesis
  • Globins / genetics
  • Hemoglobins / biosynthesis
  • Humans
  • Hydroxymethylbilane Synthase / biosynthesis
  • Hydroxymethylbilane Synthase / genetics
  • Leukemia, Erythroblastic, Acute / drug therapy*
  • Leukemia, Erythroblastic, Acute / metabolism
  • Leukemia, Erythroblastic, Acute / pathology*
  • Molecular Sequence Data
  • NF-E2 Transcription Factor
  • NF-E2 Transcription Factor, p45 Subunit
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Erythropoietin / biosynthesis
  • Receptors, Erythropoietin / genetics
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Tumor Cells, Cultured

Substances

  • Antibiotics, Antineoplastic
  • DNA-Binding Proteins
  • Erythroid-Specific DNA-Binding Factors
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • Hemoglobins
  • NF-E2 Transcription Factor
  • NF-E2 Transcription Factor, p45 Subunit
  • NFE2 protein, human
  • RNA, Messenger
  • Receptors, Erythropoietin
  • Transcription Factors
  • aclacinomycins
  • Aclarubicin
  • Doxorubicin
  • Globins
  • Hydroxymethylbilane Synthase