@misc{10481/85189,
year = {2023},
month = {8},
url = {https://hdl.handle.net/10481/85189},
abstract = {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.},
organization = {Kreftforeningen, the Norwegian Cancer Society 100933},
organization = {Research
Council of Norway 245979/F50},
organization = {Bergen Research Foundation},
organization = {NorSeq consortium, University of Bergen},
publisher = {MDPI},
keywords = {Acute myeloid leukemia},
keywords = {Vacuolar ATPase},
keywords = {Bafilomycin A1},
keywords = {Concanamycin},
keywords = {Proliferation},
keywords = {Apoptosis},
keywords = {Cytokine},
keywords = {Casein kinase 2},
keywords = {Toxicity},
title = {Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity},
doi = {10.3390/jcm12175546},
author = {Bartaula-Brevik, Sushma and Hernández Valladares, María del Carmen},
}