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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-9032553 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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