Chloroquine enhances cobalt chloride-induced leukemic cell differentiation via the suppression of autophagy at the late phase

We previously reported that moderate hypoxia and hypoxia-mimetic agents including cobalt chloride (CoCl2) induce differentiation of human acute myeloid leukemia (AML) cells through hypoxia-inducible factor-I alpha (HIF-1 alpha), which interacts with and enhances transcriptional activity of CCAAT-enhancer binding factor alpha and Runx1/AML1, two important transcriptional factors for hematopoietic cell differentiation. Here, we show that autophagy inhibitor chloroquine (CQ) increases HIF-1 alpha accumulation, thus potentiating CoCl2-induced growth arrest and differentiation of leukemic cells. Furthermore, the increased effect of CQ on differentiation induction is dependent of the inhibition of autophagosome maturation and degradation, since this sensitization could be mimicked by the suppression of expression of both lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2). These findings not only provide the evidence that CQ is a sensitizer for CoCl2-induced differentiation of leukemic cells but also possibly propose the new therapeutic strategy for differentiation induction of AML. (C) 2012 Elsevier Inc. All rights reserved.