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  • Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells.

Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells.

EMBO molecular medicine (2012-04-13)
Luigi Leanza, Brian Henry, Nicola Sassi, Mario Zoratti, K George Chandy, Erich Gulbins, Ildikò Szabò
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-PARP antibody produced in mouse, clone C-2-10, ascites fluid
Sigma-Aldrich
Psoralen, ≥99% (HPLC)
Sigma-Aldrich
Anti-LC3 antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Bak Antibody, NT, Upstate®, from rabbit
Sigma-Aldrich
Caspase 9 Colorimetric Activity Assay Kit, LEHD, Caspase-9 Colorimetric Activity Assay Kits provide a simple & convenient means for assaying the activity of caspases that recognize the LEHD.