Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells.
Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells.
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DOI：
10.18632/oncotarget.9122
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发表时间：
2016-06-07
期刊：
影响因子：
--
通讯作者：
Lisanti MP
中科院分区：
文献类型：
--
作者：
Fiorillo M;Lamb R;Tanowitz HB;Mutti L;Krstic-Demonacos M;Cappello AR;Martinez-Outschoorn UE;Sotgia F;Lisanti MP
阿托伐醌是FDA批准的抗疟疾药物，于2000年首次临床上市。目前，其主要用途是治疗免疫功能低下患者的肺孢子虫肺炎（PCP）和/或弓形虫病。阿托伐醌是泛醌的羟基-1，4-萘醌类似物，也称为辅酶Q10（CoQ 10）。它是一种耐受性良好的药物，不会引起骨髓抑制。从机制上讲，它被认为是一种有效的选择性OXPHOS抑制剂，通过靶向线粒体复合物III的辅酶Q10依赖性。在这里，我们首次表明阿托伐醌也具有抗癌活性，直接针对癌症干细胞（CSC）。更具体地说，我们证明，阿托伐醌治疗MCF 7乳腺癌细胞抑制耗氧量和代谢诱导有氧糖酵解（瓦尔堡效应），以及氧化应激。值得注意的是，阿托伐醌有效地抑制MCF 7衍生的CSC的增殖，如使用乳腺球测定所测量的，IC-50为1 μM。阿托伐醌还在CSC和非CSC的混合群体中保持这种选择性和效力。重要的是，这些结果表明糖酵解本身不足以维持CSC的增殖，而是严格依赖于线粒体功能。除了靶向CSC的增殖，阿托伐醌还在暴露于锚定非依赖性条件12小时期间诱导CD 44 +/CD 24低/− CSC和ALDH+ CSC群体的凋亡。然而，它对正常人成纤维细胞中的氧消耗没有影响，并且在这种细胞背景下，表现为抗炎，这与它在治疗感染的患者中耐受良好的事实一致。可能需要在异种移植模型和人体临床试验中进行进一步研究，因为阿托伐醌对CSC作用的IC-50（1 μM）比其人体平均血清浓度低50倍以上。
Atovaquone is an FDA-approved anti-malarial drug, which first became clinically available in the year 2000. Currently, its main usage is for the treatment of pneumocystis pneumonia (PCP) and/or toxoplasmosis in immune-compromised patients. Atovaquone is a hydroxy-1,4-naphthoquinone analogue of ubiquinone, also known as Co-enzyme Q10 (CoQ10). It is a well-tolerated drug that does not cause myelo-suppression. Mechanistically, it is thought to act as a potent and selective OXPHOS inhibitor, by targeting the CoQ10-dependence of mitochondrial complex III. Here, we show for the first time that atovaquone also has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that atovaquone treatment of MCF7 breast cancer cells inhibits oxygen-consumption and metabolically induces aerobic glycolysis (the Warburg effect), as well as oxidative stress. Remarkably, atovaquone potently inhibits the propagation of MCF7-derived CSCs, with an IC-50 of 1 μM, as measured using the mammosphere assay. Atovaquone also maintains this selectivity and potency in mixed populations of CSCs and non-CSCs. Importantly, these results indicate that glycolysis itself is not sufficient to maintain the proliferation of CSCs, which is instead strictly dependent on mitochondrial function. In addition to targeting the proliferation of CSCs, atovaquone also induces apoptosis in both CD44+/CD24low/− CSC and ALDH+ CSC populations, during exposure to anchorage-independent conditions for 12 hours. However, it has no effect on oxygen consumption in normal human fibroblasts and, in this cellular context, behaves as an anti-inflammatory, consistent with the fact that it is well-tolerated in patients treated for infections. Future studies in xenograft models and human clinical trials may be warranted, as the IC-50 of atovaquone's action on CSCs (1 μM) is >50 times less than its average serum concentration in humans.
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影响因子：
6.4
作者：
Dasgupta, Santanu;Hoque, Mohammad Obaidul;Upadhyay, Sunil;Sidransky, David
通讯作者：
Sidransky, David
影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
--
作者：
Lamb R;Ozsvari B;Lisanti CL;Tanowitz HB;Howell A;Martinez-Outschoorn UE;Sotgia F;Lisanti MP
通讯作者：
Lisanti MP
影响因子：
--
作者：
De Luca A;Fiorillo M;Peiris-Pagès M;Ozsvari B;Smith DL;Sanchez-Alvarez R;Martinez-Outschoorn UE;Cappello AR;Pezzi V;Lisanti MP;Sotgia F
通讯作者：
Sotgia F
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES