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

被引：148

作者：

Leanza, Luigi ^{[1
]}

Romio, Matteo ^{[2
]}

Becker, Katrin Anne ^{[3
]}

Azzolini, Michele ^{[4
,5
]}

Trentin, Livio ^{[6
,7
]}

Manago, Antonella ^{[1
]}

Venturini, Elisa ^{[3
]}

Zaccagnino, Angela ^{[8
,9
]}

Mattarei, Andrea ^{[2
]}

Carraretto, Luca ^{[1
]}

Urbani, Andrea ^{[1
]}

Kadow, Stephanie ^{[3
]}

Biasutto, Lucia ^{[4
,5
]}

Martini, Veronica ^{[6
,7
]}

Severin, Filippo ^{[6
,7
]}

Peruzzo, Roberta ^{[1
]}

Trimarco, Valentina ^{[6
,7
]}

Egberts, Jan-Hendrik ^{[8
,9
]}

Hauser, Charlotte ^{[8
,9
]}

Visentin, Andrea ^{[6
,7
]}

Semenzato, Gianpietro ^{[6
,7
]}

Kalthoff, Holger ^{[8
,9
]}

Zoratti, Mario ^{[4
,5
]}

Gulbins, Erich ^{[3
,10
]}

Paradisi, Cristina ^{[2
]}

Szabo, Ildiko ^{[1
,5
]}

机构：

[1] Univ Padua, Dept Biol, Viale G Colombo 3, I-35100 Padua, Italy

[2] Univ Padua, Dept Chem Sci, Via F Marzolo 1, I-35121 Padua, Italy

[3] Univ Duisburg Essen, Dept Mol Biol, Hufelandstr 55, D-45122 Essen, Germany

[4] Univ Padua, Dept Biomed Sci, I-35100 Padua, Italy

[5] CNR, Inst Neurosci, Viale G Colombo 3, I-35121 Padua, Italy

[6] Univ Padua, Dept Med, Hematol & Immunol Branch, Via G Orus 2, I-35129 Padua, Italy

[7] Venetian Inst Mol Med, Via G Orus 2, I-35129 Padua, Italy

[8] CAU, Fac Med, Inst Expt Canc Res, Campus Kiel,Arnold Heller Str 3,Haus 17, D-24105 Kiel, Germany

[9] UKSH, Dept Surg, Campus Kiel,Arnold Heller Str 3,Haus 17, D-24105 Kiel, Germany

[10] Univ Cincinnati, Dept Surg, 231 Albert Sabin Way, Cincinnati, OH 45267 USA

来源：

CANCER CELL | 2017年 / 31卷 / 04期

关键词：

KV1.3 POTASSIUM CHANNEL; CHRONIC LYMPHOCYTIC-LEUKEMIA; BAX-INDUCED APOPTOSIS; PERMEABILITY TRANSITION; CANCER-THERAPY; AUTOIMMUNE-DISEASES; T-LYMPHOCYTES; ROS RELEASE; COMPLEX-I; MECHANISMS;

D O I：

10.1016/j.ccell.2017.03.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：516 / +

页数：26

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