Mechanisms of resistance to apoptosis in human AML blasts: the role of differentiation-induced perturbations of cell-cycle checkpoints

Alterations in the response of leukaemic cells to apoptosis-inducing stimul i may account for resistance to chemotherapy and treatment failure, either by disruption of the apoptotic pathway itself or by altered DNA repair; qui escent cells and those with disrupted cell-cycle checkpoints may also displ ay decreased apoptosis. Quiescence can be induced by the differentiation of myeloid cells, and this led us to investigate whether the modulation of dr ug-induced apoptosis associated with differentiation might be a model for q uiescence-associated resistance generally. We have demonstrated that resist ance to idarubicin-induced apoptosis increased with greater duration of inc ubation of HL60 and U937 cells with ATRA and 1,25(OH)(2) D3 and that this p rotective effect correlated with the degree of G0/G1 accumulation. In addit ion, the cytoprotective effects held for other classes of cytotoxic drugs w ith different mechanisms of action to idarubicin. Prolonged exposure to ida rubicin or vinblastine was associated with diminution of the protective eff ect and re-entry of cells into cycle. The full cytoprotective effect was re stored by resupplementation with ATRA or 1,25(OH)(2) D3 during exposure to idarubicin, with concomitant persistence of G0/G1 accumulation. Differentia ting agents prevented the accumulation of leukaemic cells at the G2/M check point in response to low concentrations of idarubicin. Understanding how di fferentiating agents modulate these cell-cycle checkpoints, and how quiesce nt cells evade apoptosis, may allow the development of therapeutic strategi es to limit such apoptosis-inhibiting effects and maximise cell kill from c hemotherapy.