From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria.
From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria.
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DOI：
10.1186/s12936-015-0720-5
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发表时间：
2015-05-28
期刊：
影响因子：
3
通讯作者：
Cabrales P
中科院分区：
文献类型：
--
作者：
Yalcin O;Oronsky B;Carvalho LJ;Kuypers FA;Scicinski J;Cabrales P
疟原虫在红细胞（RBC）中大量血红素诱导的氧化应激下的存活依赖于磷酸戊糖途径（PPP）。PPP是红细胞中NADPH的唯一来源，对于还原型谷胱甘肽（GSH）的产生和保护免受氧化应激至关重要。因此，葡萄糖-6-磷酸脱氢酶（G6 PD）缺乏增加了红细胞对氧化应激的脆弱性。在疟原虫中，G6 PD与PPP的第二种酶结合产生一种独特的双功能酶，称为葡萄糖-6-磷酸脱氢酶-6-磷酸肌醇内酯酶（G6 PD-6PGL）。RRx-001是一种新型、全身无毒、表观遗传抗癌药，目前正处于针对多种肿瘤类型的2期临床开发阶段，其活性通过增加一氧化氮（NO）产生和PPP抑制介导。RRx-001可抑制G6 PD和NO的过度产生，提示其在脑型疟疾（CM）治疗中的应用。伯氏疟原虫ANKA（PlasmodiumbergheiANKA，PbA）感染C57 BL/6小鼠是一种脑型疟疾（cerebralmalaria，ECM）的实验模型，具有与人CM相似的病理特征。本研究使用活体显微镜方法与一个封闭的颅窗模型，以量化脑血流动力学的变化和白细胞粘附到内皮细胞的ECM。RRx-001既具有单药抗寄生虫活性，又显著增加蒿甲醚的功效。此外，RRx-001单独使用或与蒿甲醚联合使用可保持脑灌注并减少炎症。RRx-001的作用与PPP（G6 PD和G6 PD-6PGL）的抑制和微循环流量的改善相关，这可能与RRx-001的NO供体性质有关。结果表明，RRx-001可用于增强青蒿素的抗疟疾作用，特别是对耐药菌株，并预防感染。
The survival of malaria parasites, under substantial haem-induced oxidative stress in the red blood cells (RBCs) is dependent on the pentose phosphate pathway (PPP). The PPP is the only source of NADPH in the RBC, essential for the production of reduced glutathione (GSH) and for protection from oxidative stress. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, therefore, increases the vulnerability of erythrocytes to oxidative stress. In Plasmodium, G6PD is combined with the second enzyme of the PPP to create a unique bifunctional enzyme, named glucose-6-phosphate dehydrogenase–6-phosphogluconolactonase (G6PD-6PGL). RRx-001 is a novel, systemically non-toxic, epigenetic anticancer agent currently in Phase 2 clinical development for multiple tumour types, with activity mediated through increased nitric oxide (NO) production and PPP inhibition. The inhibition of G6PD and NO overproduction induced by RRx-001 suggested its application in cerebral malaria (CM). Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice is an experimental model of cerebral malaria (ECM) with several similar pathological features to human CM. This study uses intravital microscopy methods with a closed cranial window model to quantify cerebral haemodynamic changes and leukocyte adhesion to endothelial cells in ECM. RRx-001 had both single agent anti-parasitic activity and significantly increased the efficacy of artemether. In addition, RRx-001 preserved cerebral perfusion and reduced inflammation alone or combined with artemether. RRx-001’s effects were associated with inhibition of PPP (G6PD and G6PD-6PGL) and by improvements in microcirculatory flow, which may be related to the NO donating properties of RRx-001. The results indicate that RRx-001 could be used to potentiate the anti-malarial action of artemisinin, particularly on resistant strains, and to prevent infection.
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DOI：
10.3791/2184
发表时间：
2010-11-18
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Cabrales, Pedro;Carvalho, Leonardo J M
通讯作者：
Carvalho, Leonardo J M
影响因子：
2.3
作者：
Beutler, E;Gelbart, T;Miller, W
通讯作者：
Miller, W
影响因子：
82.9
作者：
Cosby, K;Partovi, KS;Gladwin, MT
通讯作者：
Gladwin, MT
影响因子：
5
作者：
Lackner, P;Beer, R;Schmutzhard, E
通讯作者：
Schmutzhard, E
影响因子：
3.7
作者：
Fens, Marcel H.;Larkin, Sandra K.;Kuypers, Frans A.
通讯作者：
Kuypers, Frans A.