Details

Autor(en) / Beteiligte

• Leanza, Luigi
• Romio, Matteo
• Becker, Katrin Anne
• Azzolini, Michele
• Trentin, Livio
• Managò, Antonella
• Venturini, Elisa
• Zaccagnino, Angela
• Mattarei, Andrea
• Carraretto, Luca
• Urbani, Andrea
• Kadow, Stephanie
• Biasutto, Lucia
• Martini, Veronica
• Severin, Filippo
• Peruzzo, Roberta
• Trimarco, Valentina
• Egberts, Jan-Hendrik
• Hauser, Charlotte
• Visentin, Andrea
• Semenzato, Gianpietro
• Kalthoff, Holger
• Zoratti, Mario
• Gulbins, Erich
• Paradisi, Cristina
• Szabo, Ildiko

Titel

Direct Pharmacological Targeting of a Mitochondrial Ion Channel Selectively Kills Tumor Cells In Vivo

Ist Teil von

• Cancer cell, 2017-04, Vol.31 (4), p.516-531.e10

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.3 using two mitochondria-targeted inhibitors alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death of even chemoresistant cells independently of p53 status. These inhibitors killed 98% of ex vivo primary chronic B-lymphocytic leukemia tumor cells while sparing healthy B cells. In orthotopic mouse models of melanoma and pancreatic ductal adenocarcinoma, the compounds reduced tumor size by more than 90% and 60%, respectively, while sparing immune and cardiac functions. Our work provides direct evidence that specific pharmacological targeting of a mitochondrial potassium channel can lead to ROS-mediated selective apoptosis of cancer cells in vivo, without causing significant side effects. [Display omitted] •Inhibition of a mitochondrial K+ channel (mitoKv1.3) alters mitochondrial function•Two mitochondria-targeted mitoKv1.3 inhibitors induce death of chemoresistant cells•The inhibitors reduce tumor size of melanoma and pancreatic adenocarcinoma in vivo•Immune and cardiac functions are preserved upon application of mitoKv1.3 blockers Leanza et al. show that two inhibitors that selectively target the mitochondrial potassium channel Kv1.3, which is often overexpressed in malignant cells, alter mitochondrial function, leading to ROS-mediated death of malignant cells in vitro and in vivo without overt effect on normal cells.