Atovaquone is a hydroxy-1,4-naphthoquinone analogue of ubiquinone, also known as Co-enzyme Q10 (CoQ10)[1]. Atovaquone is thought to act as a potent and selective OXPHOS inhibitor, by targeting the CoQ10-dependence of mitochondrial complex III[1]. Atovaquone also has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs)[1]. Atovaquone is an FDA-approved antimalarial drug, currently primarily used clinically to treat Pneumocystis pneumonia (PCP) and toxoplasmosis in immunocompromised patients[1].
In vitro, 5-10μM Atovaquone treatment of MCF7 breast cancer cells for 48h inhibits oxygen-consumption and metabolically induced aerobic glycolysis (the Warburg effect), as well as oxidative stress[1]. Atovaquone potently inhibited the propagation of MCF7-derived CSCs, with an IC50 of 1μM[1]. A 24h treatment with Atovaquone alleviated hypoxia in FaDu spheroids at 30μM and in HCT116 and H1299 spheroids at 20μM[2].
In vivo, oral administration of Atovaquone (50mg/kg/d) to FaDu and HCT116 xenograft mice for 7 days did not alter tumor volume but almost completely eliminated tumor hypoxia[2]. Treatment with Atovaquone (17-25mg/kg, p.o.) plus proguanil reduced parasitemia in dogs infected with Babesia gibsoni, although relapse of parasitic infection was observed[3].
References:
[1] Fiorillo M, Lamb R, Tanowitz HB, et al. Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget. 2016;7(23):34084-34099.
[2] Ashton TM, Fokas E, Kunz-Schughart LA, et al. The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nat Commun. 2016;7:12308.
[3] Iguchi A, Matsuu A, Fujii Y, Ikadai H, Hikasa Y. The in vitro interactions and in vivo efficacy of atovaquone and proguanil against Babesia gibsoni infection in dogs. Vet Parasitol. 2013;197(3-4):527-533.
Atovaquone是泛醌的羟基-1,4-萘醌类似物，也称为辅酶Q10 （CoQ10）[1]。Atovaquone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体III的CoQ10依赖性来发挥作用[1]。Atovaquone还具有抗肿瘤活性，主要针对癌症干细胞样细胞（CSCs）[1]。Atovaquone是FDA批准的抗疟疾药物，目前临床上的主要用途是治疗免疫功能低下患者的肺囊虫性肺炎（PCP）和弓形虫病[1]。
体外实验中，5-10μM Atovaquone处理MCF7乳腺癌细胞48小时会抑制细胞氧消耗，并在代谢上诱导有氧糖酵解（瓦伯格效应），同时还会引起氧化应激[1]。Atovaquone能有效抑制MCF7细胞来源的癌症干细胞的增殖，其IC50值为1μM[1]。用Atovaquone处理24小时后，在30μM浓度下可缓解FaDu细胞球的缺氧状态，在20μM浓度下可缓解HCT116和H1299细胞球的缺氧状态[2]。
体内实验中，在移植了FaDu和HCT116肿瘤细胞的小鼠中，按照50mg/kg/天的剂量，连续7天口服灌胃Atovaquone，肿瘤体积不变，但肿瘤缺氧情况几乎完全消除[2]。口服Atovaquone（17-25mg/kg）和proguanil联合治疗感染Babesia gibsoni的狗，可以缓解寄生虫血症，但观察到寄生虫感染复发[3]。