Superior effect of 9-cis retinoic acid (RA) compared with all-trans RA and 13-cis RA on the inhibition of clonogenic cell growth and the induction of apoptosis in OCI/AML-2 subclones: is the p53 pathway involved?
In the present study, the effects of 9-cis retinoic acid (RA) and 13-cis RA on acute myeloblastic leukaemia (AML) cell growth and the induction of apoptosis as well as its relationship with bcl-2 and p53 were compared with those of all-trans RA (ATRA). The study was performed with the subclones of the retinoid-sensitive OCI/AML-2 cell line. The most prominent inhibitory effect on clonogenic cell growth and morphological apoptosis was shown by 9-cis RA. In addition, Western blotting revealed the most obvious translocation of p53 from cytosol to nucleus in the case of 9-cis RA, which was the only retinoid able to change the conformation of p53 from mutational to wild type, as demonstrated by flow cytometry. There was no difference between the retinoids in the downregulation of bcl-2 as analysed by Western blotting and flow cytometry. The RA receptor (RAR)-alpha antagonist had no effect on apoptosis in any of the three retinoids studied using the annexin V method. In conclusion, this study shows that 9-cis RA was a more potent agent than ATRA or 13-cis RA in inducing growth arrest and apoptosis in the OCI/AML-2 subclones. The effect was associated with the downregulation of bcl-2 and was hardly mediated through the RAR-alpha receptor, but might be related to the activation of p53.
Department of Internal Medicine, University Hospital of Oulu, PO Box 20, 90029 Oulu, Finland. pirjo.koistinen@ppshp.fi
Pirjo
P
Koistinen
Aiping
A
Zheng
Marjaana
M
Säily
Timo
T
Siitonen
Pentti
P
Mäntymaa
Eeva-Riitta
ER
Savolainen
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005453:Fluorescence; D006801:Humans; D015474:Isotretinoin / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D014212:Tretinoin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018168:Receptors, Retinoic Acid; D016159:Tumor Suppressor Protein p53; D000077556:Alitretinoin; D014212:Tretinoin; D015474:Isotretinoin