Leanza 2016 Abstract Mito Xmas Meeting Innsbruck

Direct pharmacological targeting of a mitochondrial ion channel selectively kills melanoma cells in vivo.

Link:

Leanza L, Romio M, Becker KA, Azzolini M, Venturini E, Mattarei A, Carraretto L, Urbani A, Kadow S, Biasutto L, Zoratti M, Gulbins E, Paradisi C, Szabo I (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

Mitochondria are important oncological targets due to their crucial role in apoptosis. Our work identifies a novel therapeutic tool that simultaneously exploits both the high expression of the potassium channel Kv1.3 in the mitochondria of various types of cancer cells and the characteristic altered redox state of malignant cells, thereby leading to the selective elimination of even chemoresistant pathological cells by two mitochondria-targeted Kv1.3 inhibitors. Here we show that direct inhibition of Kv1.3 by two novel, mitochondria-targeted drugs alters mitochondrial function and leads to ROS-mediated death of even chemoresistant cells and independently of p53 status. In orthotopic mouse models of melanoma the compounds reduced tumor size by more than 90%. Instead, treatment of the animals with an antioxidant prevented the in vivo effect of the drugs. Our work thus provides direct evidence that specific pharmacological targeting of a mitochondrial channel can lead to ROS-mediated selective apoptosis of cancer cells in vivo, without causing significant side effects. Indeed, the strong tumor-reducing effects observed in melanoma and pancreatic ductal adenocarcinoma preclinical models are not accompanied by immune-depression, cardiac toxicity or histological alteration of healthy tissues. These findings thus offer the perspective of a major advance in the pharmacological treatment of melanoma.

Labels: MiParea: Pharmacology;toxicology  Pathology: Cancer  Stress:Cell death, Oxidative stress;RONS  Organism: Mouse 

Regulation: Redox state 

Event: A1, Oral 

Affiliations

Leanza L(1), Romio M(2), Becker KA(3), Azzolini M(4,5), Venturini E(3), Mattarei A(2), Carraretto L(1), Urbani A(1), , Kadow S(3), Biasutto L(4,5), Zoratti M(4,5), Gulbins E(3,8), Paradisi C(2), Szabo I(1,5)

1. Dept Biology, Univ Padova, viale G. Colombo 3, Italy
2. Dept Chemical Sc, Univ Padova, via F. Marzolo 1, Italy
3. Dept Molecular Biology, Univ Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
4. Dept Biomedical Sc, Univ Padova, viale G. Colombo 3, Italy
5. CNR Inst Neuroscience, viale G. Colombo 3, I-35121 Padova, Italy
6. Dept Medicine, Hematology Immunological Branch, Univ Padova, Venetian Inst Molecular Medicine (VIMM), via G. Orus 2, I-35129 Padova, Italy
7. Inst Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17), Germany
8. Dept Surgery, Univ Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0558, USA