Expression and Role of hERG1 Channels in Pediatric Acute Lymphoblastic Leukemias: Shortcoming of Drug Resistance by hERG1 Channel Inhibitors in Stoma-Supported Leukaemia Cell Cultures In Vitro
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...
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| Published in: | Blood Vol. 110; no. 11; p. 724 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Elsevier Inc
16-11-2007
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| Online Access: | Get full text |
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| Summary: | 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 Leukemia 18(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 Leukemia 16:1791–1798, 2002; Smith GA, et al, JBC 227:18528–18534, 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 Blood 110:1238–1250, 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 Pharmacol 56(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:
i.hERG1 K+ channels are expressed in both all the leukaemia cell lines and primary childhood B leukaemia samples;ii.the N-terminus deleted, herg1b isoform was preferentially expressed in both cell lines and primary samples;iii.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. |
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| ISSN: | 0006-4971 1528-0020 |
| DOI: | 10.1182/blood.V110.11.724.724 |