Effect of all-trans retinoic acid on chemotherapy induced apoptosis and down-regulation of Bcl-2 in human myeloid leukaemia CD34 positive cells

被引:11
作者
Ahmed, N [1 ]
Laverick, L [1 ]
Sammons, J [1 ]
Baumforth, KRN [1 ]
Hassan, HT [1 ]
机构
[1] Wolverhampton Univ, Sch Hlth Sci, Div Biomed Sci, Wolverhampton WV1 1DJ, W Midlands, England
关键词
apoptosis; Bcl-2; CD34; fludarabine; leukaemia; retinoic acid;
D O I
10.1016/S0145-2126(99)00084-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Acute myeloid leukaemia (AML) is a heterogeneous malignant disease in which disease progression at the level of CD34 positive cells has a major impact in drug resistance and relapse. The multi-drug resistance (MDR1) gene product, P-glycoprotein is expressed mainly in CD34 positive AML cells and Bcl-2 is expressed simultaneously with several putative drug resistance parameters in these cells. Bcl-2 over-expression is associated with CD34 positivity, poor response to chemotherapy and reduced overall survival in AML patients. Recently, all-trans retinoic acid (RA) has been reported to enhance cytarabine-induced apoptosis and downregulate Bcl-2 in several human myeloid leukaemia CD34 negative cells. The two CD34 positive human myeloid leukaemia cell lines: KG1 and KGla have the unique feature of expressing significant functional P-glycoprotein. Thus, the efficacy of RA in enhancing cytrabine- and fludarabine-induced apoptosis and overcoming the resistance was examined in both KG1 (CD34 + CD7 -) and KGla (CD34 + CD7 +) human myeloid leukaemia cells in the present study. Both cytarabine and fludarabine induced a dose-dependent increase in the number of apoptotic cells in both CD34 positive cell types. Interestingly, the cytarabine-induced apoptosis was significantly more than fludarabine-induced apoptosis in both cell types. All-trans RA alone failed to induce apoptosis or inhibit proliferation of either of the two human CD34 positive leukaemia cell types. However, RA enhanced cytarabine- or fludarabine-induced apoptosis and inhibition of proliferation in KG1 CD34 + CD7 - but not in KGla CD34 + CD7 + myeloid leukaemia cells. As single agents, RA, cytarabine and fludarabine reduced Bcl-2 expression in a dose-dependent manner in both cell types. Using a quantitative ELISA assay, the Bcl-2 protein concentration was reduced by 86 or 100% after 72 h of treatment with 10 mu M cytarabine or fludarabine, respectively, in both CD34 positive leukaemia cell types. The addition of RA to cytarabine enhanced its induced reduction of Bcl-2 in KG1 CD34 + CD7 - but not in KGla CD34 + CD7 + human myeloid leukaemia cells. Meanwhile, RA failed to augment fludarabine-induced reduction of Bcl-2 in both cell types. In conclusion, the present results suggest a potential role for the combination of RA and cytarabine in the treatment of refractory and/or relapsed AML patients with CD34 + CD7 - but not CD34 + CD7 + blast cells. (C) 1999 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:741 / 749
页数:9
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