Azzolini 2016 Abstract Mito Xmas Meeting Innsbruck

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Targeting a mitochondrial potassium channel as a new way to treat chronic lymphocytic leukemia.

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Azzolini M, Martini V, Severin F, Romio M, Mattarei A, Zoratti M, Trentin L, Semenzato G, Paradisi C, Leanza L, Szabo I (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

Human Chronic Lymphocytic Leukemia (B-CLL) is the most commonly diagnosed leukemia in the western world. Therapeutic options to treat this leukemia are very limited. B-CLL is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Different leukemic cells or cell lines, both myeloid and lymphoid, express/overexpress several potassium channels including shaker type voltage-gated Kv1.3, Kv11.1 (Herg), and calcium-activated KCa3.1, and their pharmacological inhibition has been related to reduced B-CLL proliferation, pointing to ion channels as promising oncological targets in B-CLL. We obtained evidence that Kv1.3 is highly expressed in B-CLL respect to normal B cells both in the plasma membrane and in the inner mitochondrial membrane. We have recently shown that the treatment with mitochondrial Kv1.3 inhibitors actively killed primary B-CLL cells in ex-vivo experiments, by induction of intrinsic apoptosis. Importantly, cells form healthy subjects and even residual normal T lymphocytes of the same patients were unaffected by the drugs, while B-CLL cells were killed. Importantly, B-CLL cell death was observed also when leukemic cells were co-cultured with mesenchymal stromal cells (MSC), which favor tumor cell growth by releasing anti-apoptotic and pro-survival factors. Here we report the first in vivo evidence, that pharmacological targeting of the mitochondrial Kv1.3 by a new mitochondrial targeted inhibitor is sufficient to lead to a massive CD5+/CD19+ elimination in several organs (blood, peritoneal cavity, spleen, bone marrow) in a B-CLL genetic mouse model (EuTCL-1), without inducing side effects and death in healthy immune cells, including cytotoxic T lymphocytes. These results open the possibility to a new therapeutical approach for this disease by directly targeting the mitochondrial channel.


Labels: MiParea: Pharmacology;toxicology  Pathology: Cancer  Stress:Cell death  Organism: Human, Mouse  Tissue;cell: Lymphocyte 




Event: Poster 


Affiliations

Azzolini M(1,2), Martini V(3), Severin F(3), Romio M(4), Mattarei A(4), Zoratti M(1,2), Trentin L(3), Semenzato G(3), Paradisi C(4), Leanza L(5), Szabò I(1,5)
  1. CNR Inst Neurosciences, Padua, Italy
  2. Dept Biomedical Sc, Univ Padua, Italy
  3. Dept Chemical Sc, Univ Padua, Italy
  4. Dept Medicine, Hematology Immunological Branch, Univ Padova, Venetian Inst for Molecular Medicine (VIMM), Padova, Italy
  5. Dept Biology, Univ Padua, Italy