The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia

被引：219

作者：

Ashton, Thomas M. ^{[1
]}

Fokas, Emmanouil ^{[1
]}

Kunz-Schughart, Leoni A. ^{[1
,2
,3
,4
]}

Folkes, Lisa K. ^{[1
]}

Anbalagan, Selvakumar ^{[1
]}

Huether, Melanie ^{[2
,3
,4
]}

Kelly, Catherine J. ^{[1
]}

Pirovano, Giacomo ^{[1
]}

Buffa, Francesca M. ^{[1
]}

Hammond, Ester M. ^{[1
]}

Stratford, Michael ^{[1
]}

Muschel, Ruth J. ^{[1
]}

Higgins, Geoff S. ^{[1
]}

McKenna, William Gillies ^{[1
]}

机构：

[1] CRUK MRC Oxford Inst Radiat Oncol, Old Rd Campus Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England

[2] Tech Univ Dresden, Fac Med, OncoRay Natl Ctr Radiat Res Oncol, POB 41, D-01307 Dresden, Germany

[3] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, POB 41, D-01307 Dresden, Germany

[4] Helmholtz Zentrum Dresden Rossendorf, Inst Radiooncol, POB 41, D-01307 Dresden, Germany

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国医学研究理事会;

关键词：

SQUAMOUS-CELL CARCINOMA; DIHYDROOROTATE DEHYDROGENASE; BC(1) COMPLEX; MOUSE-TUMORS; HUMAN PLASMA; NECK-CANCER; PHARMACOKINETICS; METFORMIN; RADIOTHERAPY; INHIBITION;

D O I：

10.1038/ncomms12308

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy.

引用

页数：13

共 48 条

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Indirect inhibition of mitochondrial dihydroorotate dehydrogenase activity by nitric oxide [J].