title: Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells.
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.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Leanza
authors.forename: Brian
authors.initials: B
authors.lastname: Henry
authors.forename: Nicola
authors.initials: N
authors.lastname: Sassi
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Ildikò
authors.initials: I
authors.lastname: Szabò
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002991:Clofazimine / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation; D005363:Ficusin / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C499898:5-(4-phenylbutoxy)psoralen; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers; C000612141:REG3A protein, human; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D002991:Clofazimine; D005363:Ficusin