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Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma
Stephanie Kadow1, Fabian Schumacher2, Melanie Kramer1
1Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
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.
Insights
New research identifies mitochondrial Kv1.3 channels as a promising target for multiple myeloma treatment. Inhibiting these channels effectively kills myeloma cells while sparing healthy ones, offering hope for a cure.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Multiple myeloma treatments are palliative, with all patients eventually relapsing.
- Novel therapies are needed for potential cure and improved survival.
Purpose of the Study:
- To investigate mitochondrial Kv1.3 channels as a therapeutic target in multiple myeloma.
- To evaluate the efficacy and resistance mechanisms of mitochondrial Kv1.3 inhibitors.
Main Methods:
- Assessed Kv1.3 expression in multiple myeloma cells.
- Tested mitochondrial Kv1.3 inhibitors (PAPTP, PCARBTP) on myeloma cell lines and patient samples.
- Investigated apoptosis pathways and multidrug resistance (MDR-1) involvement.
- Evaluated combination therapy with ABT-199 (venetoclax).
Main Results:
- Multiple myeloma cells express mitochondrial Kv1.3.
- PAPTP and PCARBTP effectively killed myeloma cells, sparing healthy bone marrow cells.
- Cell death occurred via mitochondrial apoptosis.
- MDR-1 up-regulation was identified as a resistance mechanism.
- Combination with ABT-199 showed synergistic effects, particularly in t(11;14) negative myeloma.
Conclusions:
- Mitochondrial Kv1.3 channels are druggable targets for multiple myeloma.
- Mitochondrial Kv1.3 inhibitors show potential as a novel therapeutic strategy.
- Combination therapy with venetoclax may overcome resistance in certain myeloma subtypes.
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