Hypoxia And Hypoxia Mimetic Agents Induce Differentiation And Apoptosis Of Leukemic Cells

Oxygen is not only a life-sustaining element to the existence of organism but also a key regulatory factor in cell's physiological function. Hypoxia generally refers to a lack of oxygen. In this condition, cell's growth, differentiation and apoptosis can be affected on different levels. In our previous work, we showed that non-toxic concentration of CoCl2 and DFO as well as mild hypoxia modified the in vitro differentiation in AML cell lines and some fresh leukemic cells; these two agents at higher concentrations could induce AML cells to undergo apoptosis. Based on these findings, we try to sequentially investigate the possible effects of hypoxia and hypoxia mimetic agents on leukemic cells. To this purpose, we got the following results:(1) Intermittent hypoxia prolonged survival in a leukemic cells-transplanted mouse model by inhibiting the infiltration of leukemic blast in tissues.(2) Immunohistological, flow cytometry and immunofluorence analyses showed that intermittent hypoxia significantly inhibited proliferation and induced differentiation without apoptosis induction of leukemic cells.(3) Hypoxic mimetic agents DFO and CoCl2 at higher concentrations induced leukemic cells NB4 and U937 to apoptosis involve a loss of mitochondria transmembrane potentials and caspase-3/8 activation. At the same time, these two agents also presented their hypoxia-mimetic effects by stabilizing HIF-1αprotein.(4) In no alteration of HIF-1αprotein, nitric oxide donors, metavanadate and sodium nitroprusside, significantly abrogated DFO-induced apoptosis. However, these two NO donors had no impact to the action of CoCl2 on leukemic cells.(5) Upon HIF-1αexpression, the apoptosis induced by DFO and CoCl2 could not be affected.Taken together, to study the cellular effects of hypoxia and hypoxia mimetic agents, we did some in vitro and in vivo investigations in this work. And we got original results: intermittent hypoxia significantly prolonged the survival of the transplanted leukemic mice through tumor arrest and differentiation of leukemic cells.Although both DFO and CoCl2 induced leukemic cell apoptosis by HIF-1α-independent mechanisms, DFO but not CoCl2-induced apoptosis involves NO-related signal pathways.