Document Detail

Direct evidence for the participation of bcl-2 in the regulation by retinoic acid of the Ara-C sensitivity of leukemic stem cells.
MedLine Citation:
PMID:  7564507     Owner:  NLM     Status:  MEDLINE    
All-trans retinoic acid (ATRA) increases the sensitivity of AML blast cells to cytosine arabinoside (Ara-C) or daunorubicin (DNR) when ATRA is given after drug. We have proposed that down-regulation of bcl-2 is part of the mechanism by which ATRA regulates drug sensitivity. To test this hypothesis cDNA encoding bcl-2 was transfected into cells of the continuous lines OCI/AML-2 and OCI/AML-5. Four transfectant lines were isolated; three contained transfected bcl-2 in the sense orientation (AML5-BCL2sa, AML5-BCL2sb and 2-bcl2) and one with anti-sense bcl-2(AML5-bcl2as). The presence of the transfected gene was demonstrated by Northern blot; translation of the sense transfected genes into protein was demonstrated by Western blotting. Lines with sense-oriented transfected bcl-2 were significantly less sensitive to Ara-C or H2O2 than the parental lines; the cells with anti-sense transfected genes were more sensitive than their parent but the difference did not reach statistical significance. The effect of ATRA on bcl-2 expression was compared in sense-transfected cells and their parents; by Northern blotting it was shown that the endogenous but not the transfected genes were down-regulated after ATRA exposure. The capacity of cells with transfected genes to respond to ATRA was tested by obtaining Ara-C survival curves for ATRA-treated cells. Compared to controls not exposed to ATRA, the transfected cells showed little or statistically insignificant changes in Ara-C sensitivity after ATRA treatment. We conclude that data from the transfectants provides evidence that expression of bcl-2 is a determinant of sensitivity to Ara-C and H2O2; and that the effect of ATRA on sensitivity requires the presence of bcl-2 genes in association with regulatory elements.
Z B Hu; M D Minden; E A McCulloch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Leukemia     Volume:  9     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  1995 Oct 
Date Detail:
Created Date:  1995-11-07     Completed Date:  1995-11-07     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1667-73     Citation Subset:  IM    
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada.
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MeSH Terms
Acute Disease
Antineoplastic Agents / pharmacology*
Cell Survival
Cytarabine / pharmacology*
Drug Resistance, Neoplasm / genetics
Hydrogen Peroxide / pharmacology*
Leukemia, Myeloid / drug therapy*
Oncogenes / drug effects,  physiology*
Proto-Oncogene Proteins / genetics,  metabolism
Proto-Oncogene Proteins c-bcl-2
Tretinoin / pharmacology*
Tumor Cells, Cultured
Tumor Stem Cell Assay
Reg. No./Substance:
0/Antineoplastic Agents; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 147-94-4/Cytarabine; 302-79-4/Tretinoin; 7722-84-1/Hydrogen Peroxide

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