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

Cancer cell | Apr 10, 2017

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.

Pubmed ID: 28399409 RIS Download

Mesh terms: Aged | Animals | Antineoplastic Agents | Carcinoma, Pancreatic Ductal | Case-Control Studies | Coumarins | Drug Stability | Female | Humans | Kv1.3 Potassium Channel | Leukemia, Lymphocytic, Chronic, B-Cell | Male | Melanoma | Mice, Inbred C57BL | Middle Aged | Mitochondria | Molecular Targeted Therapy | Organophosphorus Compounds | Pancreatic Neoplasms | Potassium Channel Blockers

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