In:
Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 724-724
Abstract:
Therapy resistance is still a major obstacle to successful treatment in a significant number of pediatric acute lymphoblastic leukaemia (ALL) patients. It has been previously demonstrated that children with ALL whose leukemia cells exhibit in vitro resistance to single or a combination of drugs have a significantly worse prognosis compared to patients with sensitive leukemic cells (Ramakers-van Woerden N, et al Leukemia18(3):521–9 2004). Ion channels are becoming one of the potential targets for cancer therapy and putative biochemical modulators of conventional chemotherapy (Conti M, J Exp Ther Oncol. 4(2):161–6, 2004). In particular, K+ channels belonging to the hERG1 family are attracting most attention, since they are over-expressed in a broad range of primary acute myeloid leukaemias (AML) as well as in both myeloid and lymphoid leukemic cell lines (Pillozzi S, et al Leukemia16:1791–1798, 2002; Smith GA, et al, JBC227:18528–18534, 2002). hERG1 channel expression confers a greater capacity to engraft the bone marrow and invade the bloodstream in NOD/SCID mice injected with AML cells. This fact corresponds to a greater malignancy (shorter overall survival and higher probability to relapse) in hERG1 positive AML patients (Pillozzi S, et al Blood110:1238–1250, 2007). It was also recently shown that the expression of hERG1 is related to the chemosensitivity of cancer cells to vincristine, paclitaxel, and hydroxy-camptothecin (Chen SZ, et al Cancer Chemother Pharmacol56(2):212–20, 2005). We studied the expression and role of hERG1 channels in various B lymphoid leukaemia cell lines and primary childhood B lymphoid leukaemia samples. It emerged that: hERG1 K+ channels are expressed in both all the leukaemia cell lines and primary childhood B leukaemia samples; the N-terminus deleted, herg1b isoform was preferentially expressed in both cell lines and primary samples; in childhood leukaemia patients, the level of herg1b expression correlated with response to therapy. B lymphoid leukaemia cell lines were co-cultured on human bone marrow stromal cells, a system known to enhance leukaemia cell survival and escape from drug-induced apoptosis. In these cultures, the addition of a specific hERG1 inhibitor, E4031, induced a significant apoptosis in leukaemia cells, bypassing the protective effect of the bone marrow microenvironment. We hypothesise that hERG1 channels can represent a novel molecular device regulating drug sensitivity in childhood acute leukaemia cells, and that targeting of hERG1 channels can restore a proper pro-apoptotic response to chemotherapy in resistant B lymphoid leukemic cells.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V110.11.724.724
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2007
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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