| Autor: |
Bartaula-Brevik S; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Leitch C; Department of Clinical Science, Centre for Pharmacy, University of Bergen, 5015 Bergen, Norway., Hernandez-Valladares M; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.; The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway.; The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.; Department of Physical Chemistry, University of Granada, Avenida de la Fuente Nueva S/N, 18071 Granada, Spain.; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain., Aasebø E; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.; The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway.; The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway., Berven FS; The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway.; The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway., Selheim F; The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway.; The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway., Brenner AK; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Rye KP; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Hagen M; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Reikvam H; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.; Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway., McCormack E; Department of Clinical Science, Centre for Pharmacy, University of Bergen, 5015 Bergen, Norway., Bruserud Ø; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.; Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway., Tvedt THA; Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.; Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway. |
| Abstrakt: |
Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients. |
