[Effects of interferon-gamma combined with all-trans retinoic acid on proliferation and differentiation of leukemia cell lines NB4 and MR2].
OBJECTIVE
More than 90% patients with acute promyelocytic leukemia (APL) achieve clinical complete remission by using all-trans retinoic acid (ATRA). However, the rapid development of ATRA-resistance has become a problem in treating APL. Many researches indicate that the mechanism of ATRA-resistance is related to lack of some proteins synthesized by interferon (IFN). This study was to explore the possibility and the possible mechanism of treating ATRA-resistant APL with IFN in combination with ATRA.


METHODS
Interferon-gamma (IFNgamma) alone or IFNgamma combined with ATRA was used to treat ATRA-sensitive cell line NB4 and ATRA-resistant cell line MR2. Cell proliferation was tested by MTT assay. Light microscope and NBT test were used to evaluate cell differentiation. The expression of promyelocytic leukemia (PML) protein was observed by indirect immune fluorescent method.


RESULTS
On the 8th day, the growth inhibition rates of NB4 cells and MR2 cells were significantly higher in combination group than in IFNgamma group and ATRA group (95.2% vs. 68.0% and 85.0%, P<0.05; 51.5% vs. 24.1% and 4.3%, P<0.05). On the 3rd day, the positive rates of NBT in NB4 cells and MR2 cells were significantly higher in combination group than in IFNgamma group and ATRA group (93.3% vs. 19.3% and 74.7%, P<0.05; 31.5% vs. 16.8% and 5.2%, P<0.05). After treatment of IFNgamma, the fluorescent particles in NB4 and MR2 cell nuclei were obviously increased as compared with those in control group.


CONCLUSIONS
IFNgamma and ATRA have synergistic inhibitory effect on the proliferation of NB4 cells and MR2 cells, and can partially induce the differentiation of ATRA-resistant MR2 cells.
He
Peng-Cheng
PC
Department of Hematology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China.
Zhang
Mei
M
Wu
Di
D
Xu
Hui
H
Cai
Rui-Bo
RB
Liu
Ya-Lin
YL
D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin; D007371:Interferon-gamma