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Clofazimine, Psora-4 and PAP-1, inhibitors of the potassium channel Kv1.3, as a new and selective therapeutic strategy in chronic lymphocytic leukemia

Leukemia volume 27, pages 1782–1785 (2013)Cite this article

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Therapeutic options to treat chronic lymphocytic leukemia (B-CLL) are at present unsatisfactory. In the present work, we provide the rationale for using clofazimine, which exhibits a very good safety profile and is already used to cure leprosy. Clofazimine might represent a novel treatment for B-CLL, which is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Ion channels are involved in different aspects of tumor progression due to their ability to regulate proliferation, apoptosis and migration. The expression of the shaker-type Kv1.3 potassium channel differs in various cancer tissues1 and the quantity of Kv1.3 mRNA was found to be slightly higher in B-CLL cells than in B cells from healthy people.2 Kv1.3, which is crucial for proliferation,3 may confer a survival advantage on proliferating cancer cells.

We and others have previously shown that Kv1.3 is expressed both in the plasma membrane (PM) and in the inner mitochondrial membrane.4 Furthermore, in several cell lines, the expression of Kv1.3 in the PM correlates with its expression in the mitochondria.5, 6 We have also previously identified mitochondrial Kv1.3 (mtKv1.3) as a target of Bax and demonstrated physical interaction between the two proteins in apoptotic cells.7, 8 Incubating Kv1.3-positive-isolated mitochondria with Bax triggered apoptotic events including mitochondrial membrane depolarization, reactive oxygen species (ROS) production and cytochrome c release, whereas Kv1.3-deficient mitochondria were resistant. Psora-4, PAP-1 and clofazimine, three distinct membrane-permeant inhibitors of Kv1.3, induced death by directly targeting the mitochondrial channel in multiple human and mouse cancer cell lines.5 Importantly, these drugs activated the intrinsic apoptotic pathway also in the absence of Bax and Bak. Genetic deficiency or siRNA-mediated downregulation of Kv1.3 abrogated the effects of the drugs, providing specificity of their action via Kv1.3. Clofazimine reduced tumor size by 90% in an orthotopic melanoma mouse model in vivo.5

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Acknowledgements

We are grateful to Professor Cristina Paradisi and Dr Andrea Mattarei for providing Q-7BPTI, and to Cristina Gattazzo and Valentina Trimarco for help with the isolation of B cells. We thank Professor G Chandy for useful discussions. We are grateful to the funding agencies supporting our work. The following are specifically acknowledged: an Italian Association for Cancer Research grant (to IS no. 11814 and to GS), an European Molecular Biology Organization Young Investigator Program grant (to IS), Progetti di Rilevante Interesse Nazionale grants (to MZ and GS), DFG-grant Gu 335/13–3 (to EG), Fondazione Cassa di Risparmio di Padova e Rovigo (CARIPARO) grants (to MZ and GS) and a Cariverona grant (to GS). This work was supported also by grants from the Regione Veneto on chronic lymphocytic leukemia (to LT and GS). This work is dedicated to Drs G Franchin and E Vaccher of CRO of Aviano.

Authors’ contribution

LL, KAB, FF, EG and IS performed the experiments; LL, LT, MZ, GS, EG and IS designed the research; IS, EG, MZ, LL, LT and GS analyzed the data and wrote the manuscript.

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The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Biology, University of Padua, Padua, Italy

    L Leanza & I Szabo

  2. Department of Medicine, Hematology and Immunological Branch, University of Padua, Venetian Institute for Molecular Medicine (VIMM), Padua, Italy

    L Trentin, F Frezzato & G Semenzato

  3. Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany

    K A Becker & E Gulbins

  4. CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padua, Padua, Italy

    M Zoratti

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  1. L Leanza
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Correspondence to I Szabo.

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Leanza, L., Trentin, L., Becker, K. et al. Clofazimine, Psora-4 and PAP-1, inhibitors of the potassium channel Kv1.3, as a new and selective therapeutic strategy in chronic lymphocytic leukemia. Leukemia 27, 1782–1785 (2013). https://doi.org/10.1038/leu.2013.56

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