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 stimuli may account for resistance to chemotherapy and treatment failure, either by disruption of the apoptotic pathway itself or by altered DNA repair; quiescent cells and those with disrupted cell-cycle checkpoints may also display decreased apoptosis. Quiescence can be induced by the differentiation of myeloid cells, and this led us to investigate whether the modulation of drug-induced apoptosis associated with differentiation might be a model for quiescence-associated resistance generally. We have demonstrated that resistance to idarubicin-induced apoptosis increased with greater duration of incubation of HL60 and U937 cells with ATRA and 1,25(OH)2 D3 and that this protective effect correlated with the degree of G0/G1 accumulation. In addition, the cytoprotective effects held for other classes of cytotoxic drugs with different mechanisms of action to idarubicin. Prolonged exposure to idarubicin or vinblastine was associated with diminution of the protective effect and re-entry of cells into cycle. The full cytoprotective effect was restored by resupplementation with ATRA or 1,25(OH)2 D3 during exposure to idarubicin, with concomitant persistence of G0/G1 accumulation. Differentiating agents prevented the accumulation of leukaemic cells at the G2/M checkpoint in response to low concentrations of idarubicin. Understanding how differentiating agents modulate these cell-cycle checkpoints, and how quiescent cells evade apoptosis, may allow the development of therapeutic strategies to limit such apoptosis-inhibiting effects and maximise cell kill from chemotherapy.
Ketley
N J
NJ
Department of Haematology, St Bartholomews and the Royal London School of Medicine and Dentistry, UK.
Allen
P D
PD
Kelsey
S M
SM
Newland
A C
AC
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D016193:G1 Phase / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells / Q000187:drug effects / Q000473:pathology; D014747:Vinblastine / Q000494:pharmacology*
D014212:Tretinoin; D014747:Vinblastine; D002117:Calcitriol; D015255:Idarubicin