DMSO-like rapid decrease in c-myc and c-myb mRNA levels and induction of differentiation in HL-60 cells by the anthracycline antitumor antibiotic aclarubicin.
The anthracycline antitumor antibiotic aclarubicin is known to induce granulocytic differentiation in the human myeloid leukemia cell line HL-60. We investigated whether this effect is accompanied by changes in the expression of the protooncogenes c-myc and c-myb. Treatment of HL-60 cells with aclarubicin, 50 nM, caused a rapid decrease in c-myc and c-myb mRNA levels within 1 h and 2 h, respectively. In parallel, we demonstrated a strong induction of superoxide-anion production on day 8 of treatment. The kinetics of the effect of aclarubicin on c-myc and c-myb expression were comparable to those associated with the dimethylsulfoxide-induced granulocytic differentiation in this cell line, or to those observed following a chase with actinomycin D, 4 microM. Since aclarubicin partially inhibited total- and poly(A)(+)-RNA synthesis, this macromolecular synthesis inhibition may be causally related to the decrease in c-myc and c-myb mRNA levels. In contrast, the conventional anthracycline doxorubicin, which did not initiate differentiation, failed to affect c-myc or c-myb mRNA levels even in high cytotoxic concentrations, indicating that the suppression of c-myc and c-myb mRNA levels may be an early differentiation-related effect of aclarubicin. On the other hand, actinomycin D, 12.5 nM, and novobiocin, 300 microM, two other known inducers of granulocytic differentiation in HL-60 cells, did not induce an early decrease in c-myb or c-myc expression. Therefore, the immediate suppression of c-myc and c-myb mRNA levels, apparently, is not an obligatory step in chemically induced myeloid differentiation in HL-60 cells, but the common phenomenon in DMSO- and aclarubicin-induced differentiation.
Stöcker
U
U
Department of Toxicology, Hamburg University Medical School, Germany.
Schaefer
A
A
Marquardt
H
H
D015250:Aclarubicin / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D016259:Genes, myc / Q000187:drug effects*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology*; D009675:Novobiocin / Q000494:pharmacology; D009857:Oncogenes / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis* / Q000096:biosynthesis; D013481:Superoxides / Q000378:metabolism
D012333:RNA, Messenger; D013481:Superoxides; D009675:Novobiocin; D003609:Dactinomycin; D015250:Aclarubicin; D004317:Doxorubicin; D004121:Dimethyl Sulfoxide