Abstract
BackgroundDaunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of cell death, including apoptosis. Apoptosis is highly regulated programmed cell death that can be initiated mainly via two pathways, through death receptors (extrinsic) or involvement of the mitochondria (intrinsic). Induction of apoptosis via these pathways has been alluded following treatment with daunorubicin, but never compared in acute lymphoblastic leukaemia over a time course.MethodsThis study investigated the mechanisms of daunorubicin induced apoptosis in the treatment of CCRF-CEM, MOLT-4 (acute T-lymphoblastic leukaemia) and SUP-B15 (acute B-lymphoblastic leukaemia) cells. Cells were treated with daunorubicin for 4 h, and then placed in recovery medium (without daunorubicin) for 4 h, 12 h and 24 h. Apoptotic response was analysing using annexin-V expression, caspase activity, mitochondrial membrane potential change and an array to detect 43 apoptotic proteins.ResultsDaunorubicin induced apoptosis in all leukemic cell lines, but with different levels and duration of response. Both apoptosis levels and caspase activity increased after four hours recovery then declined in CCRF-CEM and MOLT-4 cells. However, SUP-B15 cells displayed initially comparable levels but remained elevated over the 24 h assessment period. Changes in mitochondrial membrane potential occurred in both MOLT-4 and CCRF-CEM cells but not in SUP-B15 cells. Expression of apoptotic proteins, including Bcl-2, Bax, caspase 3 and FADD, indicated that daunorubicin potentially induced both extrinsic and intrinsic apoptosis in both CCRF-CEM and MOLT-4 cells, but only extrinsic apoptosis in SUP-B15 cells.ConclusionsThis study describes variations in sensitivities and timing of apoptotic responses in different leukaemia cell lines. These differences could be attributed to the lack of functional p53 in coordinating the cells response following cytotoxic treatment with daunorubicin, which appears to delay apoptosis and utilises alternative signalling mechanisms that need to be further explored.
Highlights
Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia
This study aims to assess the mechanisms of daunorubicin induced apoptosis in three different leukaemia cells lines: MOLT-4 and CCRF-CEM and SUP-B15
CCRF-CEM cells show a similar response to daunorubicin treatment to MOLT-4 cells
Summary
Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. Induction of apoptosis via these pathways has been alluded following treatment with daunorubicin, but never compared in acute lymphoblastic leukaemia over a time course. Understanding how the cell death program is engaged following treatment, and why it fails to be initiated in certain cancer types, is crucial in overcoming clinical problems of drug resistance. Daunorubicin is an anthracycline antibiotic which is widely used clinically in myeloma, acute lymphoblastic leukaemia (ALL) and myeloid leukemias [1] and has a broad range of therapeutic mechanisms with several toxic outcomes, and can potentially induce various types of cell death involving different regulatory pathways. Daunorubicin induced apoptotic and necrotic death of acute leukaemia cells through changes in mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) generation, which promoted mitochondria membrane permeabilization and subsequent induction of apoptosis [2]. To unravel the exact pathway of apoptosis in response to daunorubicin, it is necessary to look more closely at the intracellular mechanisms being activated
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