Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers.
Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers.
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DOI：
10.3390/cancers14092297
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发表时间：
2022-05-05
期刊：
影响因子：
5.2
通讯作者：
Barroilhet, Lisa M.
中科院分区：
文献类型：
--
作者：
Kapur, Arvinder;Mehta, Pooja;Simmons, Aaron D.;Ericksen, Spencer S.;Mehta, Geeta;Palecek, Sean P.;Felder, Mildred;Stenerson, Zach;Nayak, Amruta;Dominguez, Jose Maria Ayuso;Patankar, Manish;Barroilhet, Lisa M.
癌细胞中的Warburg效应（高葡萄糖更新和乳酸释放）是一种适应，被认为是大多数肿瘤的标志。阻断氧化磷酸化是对抗致癌作用的一种方法。阿托伐醌是线粒体复合体III抑制剂。它目前被fda批准用于治疗疟疾，是一种耐受性良好的口服药物。本实验室对阿托伐醌在妇科肿瘤中的抗癌作用进行了研究。我们发现阿托伐醌在细胞系和小鼠模型中都能减缓卵巢癌的生长。其他的抗癌效果也被观察到，比如植入小鼠体内的癌症干细胞和球体的增殖减少。阿托伐醌抑制氧消耗和ATP的产生。代谢研究表明，阿托伐醌改变了糖酵解、电子传递和柠檬酸循环。我们的研究提供了机制理解和临床前数据，支持进一步研究阿托伐酮作为妇科癌症治疗的潜力。氧化磷酸化在癌症中是一个活跃的代谢途径。阿托伐醌是一种口服药物，可抑制氧化磷酸化作用，fda批准用于治疗疟疾。我们通过测量二维培养中的细胞增殖来研究其潜在的抗癌特性。临床配方的阿托伐醌，美普龙，给予小鼠卵巢癌，以监测其对肿瘤和腹水的影响。用阿托伐醌治疗NSG小鼠的患者源性癌症干细胞和球体。体外和体内实验结果表明，阿托伐醌能抑制肿瘤细胞的增殖和卵巢癌的生长。采用流式细胞术和成像细胞术观察阿托伐醌对氧自由基的影响。用海马XFe96细胞外通量分析仪测定贴壁细胞的耗氧量（OCR）。阿托伐醌抑制氧消耗和ATP的产生。成像细胞术显示，阿托伐酮引起的氧自由基通量主要发生在线粒体。阿托伐醌可降低NSG小鼠体内患者源性癌症干细胞样细胞和球体的活力。核磁共振代谢组学显示，在阿托伐酮治疗后，糖酵解、柠檬酸循环、电子传递链、磷转移和代谢发生了变化。我们的研究提供了机制的理解和临床前数据，以支持进一步研究阿托伐酮作为妇科癌症治疗的潜力。
The Warburg effect in cancer cells (high glucose update and lactate release) is an adaptation that is considered a hallmark of most neoplasms. Blocking oxidative phosphorylation is one way to combat carcinogenesis. Atovaquone is a mitochondrial complex III inhibitor. It is currently FDA-approved for the treatment of malaria, and is a well-tolerated, orally available medication. Our laboratory studied the anti-cancer properties of atovaquone in gynecologic cancers. We found that atovaquone slowed ovarian cancer growth in both cell lines and mouse models. Additional anti-cancer effects were seen, such as the reduced proliferation of cancer stem cells and spheroids implanted in mice. Atovaquone inhibited oxygen consumption and ATP production. Metabolic studies showed that atovaquone shifted glycolysis, electronic transport and the citric acid cycle. Our studies provided the mechanistic understanding and preclinical data to support the further investigation of atovaquone’s potential as a cancer therapy for gynecologic cancers. Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone’s potential as a gynecologic cancer therapeutic.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
DOI：
10.1038/nrm3772
发表时间：
2014-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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氧化应激的调节以及随后诱导的凋亡和内质网应激使柠檬质减少癌细胞增殖。
影响因子：
4.6
作者：
Kapur A;Felder M;Fass L;Kaur J;Czarnecki A;Rathi K;Zeng S;Osowski KK;Howell C;Xiong MP;Whelan RJ;Patankar MS
通讯作者：
Patankar MS
影响因子：
--
作者：
Deng J;Wang L;Chen H;Hao J;Ni J;Chang L;Duan W;Graham P;Li Y
通讯作者：
Li Y
影响因子：
5.8
作者：
Parkes, Eileen E.;Kennedy, Richard D.
通讯作者：
Kennedy, Richard D.