Azzolini 2016 Abstract Mito Xmas Meeting Innsbruck
Targeting a mitochondrial potassium channel as a new 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, SzabΓ² 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.
β’ O2k-Network Lab: RU Moscow Skulachev VP
Labels:
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), SzabΓ² I(1,5)
- CNR Inst Neurosciences, Padua, Italy
- Dept Biomedical Sc, Univ Padua, Italy
- Dept Chemical Sc, Univ Padua, Italy
- Dept Medicine, Hematology Immunological Branch, Univ Padova, Venetian Inst for Molecular Medicine (VIMM), via G. Orus 2, I-35129 Padova, Italy
- Dept Biology, Univ Padua, Italy