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Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma is a non-curable disease and new therapeutic approaches are needed. PAPTP and PCARBTP, two novel mitochondria-specific inhibitors of the Kv1.3 ion channel, are effective in killing cultured myeloma cell lines and myeloma cells isolated from patient punctates, while h...

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Autores principales: Kadow, Stephanie, Schumacher, Fabian, Kramer, Melanie, Hessler, Gabriele, Scholtysik, René, Oubari, Sara, Johansson, Patricia, Hüttmann, Andreas, Reinhardt, Hans Christian, Kleuser, Burkhard, Zoratti, Mario, Mattarei, Andrea, Szabò, Ildiko, Gulbins, Erich, Carpinteiro, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032553/
https://www.ncbi.nlm.nih.gov/pubmed/35454865
http://dx.doi.org/10.3390/cancers14081955
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author Kadow, Stephanie
Schumacher, Fabian
Kramer, Melanie
Hessler, Gabriele
Scholtysik, René
Oubari, Sara
Johansson, Patricia
Hüttmann, Andreas
Reinhardt, Hans Christian
Kleuser, Burkhard
Zoratti, Mario
Mattarei, Andrea
Szabò, Ildiko
Gulbins, Erich
Carpinteiro, Alexander
author_facet Kadow, Stephanie
Schumacher, Fabian
Kramer, Melanie
Hessler, Gabriele
Scholtysik, René
Oubari, Sara
Johansson, Patricia
Hüttmann, Andreas
Reinhardt, Hans Christian
Kleuser, Burkhard
Zoratti, Mario
Mattarei, Andrea
Szabò, Ildiko
Gulbins, Erich
Carpinteiro, Alexander
author_sort Kadow, Stephanie
collection PubMed
description SIMPLE SUMMARY: Multiple myeloma is a non-curable disease and new therapeutic approaches are needed. PAPTP and PCARBTP, two novel mitochondria-specific inhibitors of the Kv1.3 ion channel, are effective in killing cultured myeloma cell lines and myeloma cells isolated from patient punctates, while healthy bone marrow cells are not affected. Cell death occurs through the classical mitochondrial apoptotic pathway, and further treatment with venetoclax, a BCL-2 inhibitor, has a clear synergistic effect. We identify Kv1.3 channels as a new therapeutic target for the treatment of multiple myeloma. ABSTRACT: Despite several new developments in the treatment of multiple myeloma, all available therapies are only palliative without curative potential and all patients ultimately relapse. Thus, novel therapeutic options are urgently required to prolong survival of or to even cure myeloma. Here, we show that multiple myeloma cells express the potassium channel Kv1.3 in their mitochondria. The mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP are efficient against two tested human multiple myeloma cell lines (L-363 and RPMI-8226) and against ex vivo cultured, patient-derived myeloma cells, while healthy bone marrow cells are spared from toxicity. Cell death after treatment with PAPTP and PCARBTP occurs via the mitochondrial apoptotic pathway. In addition, we identify up-regulation of the multidrug resistance pump MDR-1 as the main potential resistance mechanism. Combination with ABT-199 (venetoclax), an inhibitor of Bcl2, has a synergistic effect, suggesting that mitochondrial Kv1.3 inhibitors could potentially be used as combination partner to venetoclax, even in the treatment of t(11;14) negative multiple myeloma, which represent the major part of cases and are rather resistant to venetoclax alone. We thus identify mitochondrial Kv1.3 channels as druggable targets against multiple myeloma.
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spelling pubmed-90325532022-04-23 Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma Kadow, Stephanie Schumacher, Fabian Kramer, Melanie Hessler, Gabriele Scholtysik, René Oubari, Sara Johansson, Patricia Hüttmann, Andreas Reinhardt, Hans Christian Kleuser, Burkhard Zoratti, Mario Mattarei, Andrea Szabò, Ildiko Gulbins, Erich Carpinteiro, Alexander Cancers (Basel) Article SIMPLE SUMMARY: Multiple myeloma is a non-curable disease and new therapeutic approaches are needed. PAPTP and PCARBTP, two novel mitochondria-specific inhibitors of the Kv1.3 ion channel, are effective in killing cultured myeloma cell lines and myeloma cells isolated from patient punctates, while healthy bone marrow cells are not affected. Cell death occurs through the classical mitochondrial apoptotic pathway, and further treatment with venetoclax, a BCL-2 inhibitor, has a clear synergistic effect. We identify Kv1.3 channels as a new therapeutic target for the treatment of multiple myeloma. ABSTRACT: Despite several new developments in the treatment of multiple myeloma, all available therapies are only palliative without curative potential and all patients ultimately relapse. Thus, novel therapeutic options are urgently required to prolong survival of or to even cure myeloma. Here, we show that multiple myeloma cells express the potassium channel Kv1.3 in their mitochondria. The mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP are efficient against two tested human multiple myeloma cell lines (L-363 and RPMI-8226) and against ex vivo cultured, patient-derived myeloma cells, while healthy bone marrow cells are spared from toxicity. Cell death after treatment with PAPTP and PCARBTP occurs via the mitochondrial apoptotic pathway. In addition, we identify up-regulation of the multidrug resistance pump MDR-1 as the main potential resistance mechanism. Combination with ABT-199 (venetoclax), an inhibitor of Bcl2, has a synergistic effect, suggesting that mitochondrial Kv1.3 inhibitors could potentially be used as combination partner to venetoclax, even in the treatment of t(11;14) negative multiple myeloma, which represent the major part of cases and are rather resistant to venetoclax alone. We thus identify mitochondrial Kv1.3 channels as druggable targets against multiple myeloma. MDPI 2022-04-13 /pmc/articles/PMC9032553/ /pubmed/35454865 http://dx.doi.org/10.3390/cancers14081955 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kadow, Stephanie
Schumacher, Fabian
Kramer, Melanie
Hessler, Gabriele
Scholtysik, René
Oubari, Sara
Johansson, Patricia
Hüttmann, Andreas
Reinhardt, Hans Christian
Kleuser, Burkhard
Zoratti, Mario
Mattarei, Andrea
Szabò, Ildiko
Gulbins, Erich
Carpinteiro, Alexander
Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma
title Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma
title_full Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma
title_fullStr Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma
title_full_unstemmed Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma
title_short Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma
title_sort mitochondrial kv1.3 channels as target for treatment of multiple myeloma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032553/
https://www.ncbi.nlm.nih.gov/pubmed/35454865
http://dx.doi.org/10.3390/cancers14081955
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