Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak‐independent death of cancer cells
Open Access
- 11 April 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 4 (7), 577-593
- https://doi.org/10.1002/emmm.201200235
Abstract
Overcoming the resistance of tumours to chemotherapy, often due to downregulation of Bax and Bak, represents a significant clinical challenge. It is therefore important to identify novel apoptosis inducers that bypass Bax and Bak. Potassium channels are emerging as oncological targets and a crucial role of mitochondrial Kv1.3 in apoptosis has been demonstrated. Here we report for the first time that Psora‐4, PAP‐1 and clofazimine, three distinct membrane‐permeant inhibitors of Kv1.3, induce death by directly targeting the mitochondrial channel in multiple human and mouse cancer cell lines. Importantly, these drugs activated the intrinsic apoptotic pathway also in the absence of Bax and Bak, a result in agreement with the current mechanistic model for mitochondrial Kv1.3 action. Genetic deficiency or short interfering RNA (siRNA)‐mediated downregulation of Kv1.3 abrogated the effects of the drugs. Intraperitoneal injection of clofazimine reduced tumour size by 90% in an orthotopic melanoma B16F10 mouse model in vivo, while no adverse effects were observed in several healthy tissues. The study indicates that inhibition of mitochondrial Kv1.3 might be a novel therapeutic option for the induction of cancer cell death independent of Bax and Bak.Keywords
This publication has 62 references indexed in Scilit:
- Single-point mutations of a lysine residue change function of Bax and Bcl-xL expressed in Bax- and Bak-less mouse embryonic fibroblasts: novel insights into the molecular mechanisms of Bax-induced apoptosisCell Death & Differentiation, 2010
- Kv1.3 is the exclusive voltage-gated K+channel of platelets and megakaryocytes: roles in membrane potential, Ca2+signalling and platelet countThe Journal of Physiology, 2010
- Methods in Mammalian Autophagy ResearchCell, 2010
- The functional network of ion channels in T lymphocytesImmunological Reviews, 2009
- Kv1.1 and Kv1.3 channels contribute to the degeneration of retinal ganglion cells after optic nerve transection in vivoCell Death & Differentiation, 2009
- Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T LymphocytesPLOS ONE, 2008
- Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytesProceedings of the National Academy of Sciences of the United States of America, 2008
- ROS stress in cancer cells and therapeutic implicationsDrug Resistance Updates, 2004
- BAX and BAK Regulation of Endoplasmic Reticulum Ca 2+ : A Control Point for ApoptosisScience, 2003
- Distinct types of diffuse large B-cell lymphoma identified by gene expression profilingNature, 2000