Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor Imatinib.
Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor Imatinib.
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DOI：
10.1016/j.ijpddr.2014.07.005
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发表时间：
2014-12
影响因子：
4
通讯作者：
Grevelding, Christoph G.
中科院分区：
文献类型：
--
作者：
Beckmann, Svenja;Long, Thavy;Scheld, Christina;Geyer, Rudolf;Caffrey, Conor R.;Grevelding, Christoph G.
关键词：
Abl酪氨酸激酶抑制剂伊马替尼对S. mansoni，但在啮齿类动物体内没有。血清白蛋白和α-1酸性糖蛋白（AGP）等血液成分在体外消除了伊马替尼的毒性。红霉素在体外部分恢复了伊马替尼的毒性。感染后高水平的AGP使啮齿动物成为检查一些小分子抑制剂的不良模型。在寻找治疗扁形虫病血吸虫病的新药物和药物靶点的过程中，蛋白激酶（PKs）受到特别的关注，因为它们在寄生虫的发育和生理过程中发挥着重要作用。在这种情况下，抗癌Abl酪氨酸激酶（TK）抑制剂伊马替尼（格列卫/格列卫; STI-571）在体外对曼氏血吸虫成虫的应用已经表明对包括存活在内的多种生理过程的负面影响。受这些体外研究结果的启发，我们在啮齿动物S.曼氏感染。出乎意料的是，伊马替尼对蠕虫负担或产卵没有影响。我们发现，血液成分血清白蛋白（SA）和α-1酸性糖蛋白（AGP或orosomucoid）否定了伊马替尼对成年S。mansoni和童虫（感染后幼虫）。这种负面影响被红霉素部分逆转。AGP合成可由于炎症过程或感染而增加;此外，在感染后，小鼠中的AGP水平比人类高6-8倍。因此，小鼠和其他啮齿动物可能是用于测量伊马替尼体内作用的不良感染模型。因此，我们建议在费力和昂贵的动物实验之前，对AGP和SA阻断小分子如伊马替尼的体外抗溶酶体作用的能力进行常规评估。
The Abl tyrosine-kinase inhibitor Imatinib is toxic to S. mansoni in vitro but not in vivo in rodents. Blood components like serum albumin and alpha-1 acid glycoprotein (AGP) negated Imatinib’s toxicity in vitro. Erythromycin partially restored the toxicity of Imatinib in vitro. High levels of AGP upon infection make rodents poor models for examining some small molecule inhibitors. In the search for new drugs and drug targets to treat the flatworm disease schistosomiasis, protein kinases (PKs) have come under particular scrutiny because of their essential roles in developmental and physiological processes in schistosome parasites. In this context the application of the anti-cancer Abl tyrosine kinase (TK) inhibitor Imatinib (Gleevec/Glivec; STI-571) to adult Schistosoma mansoni in vitro has indicated negative effects on diverse physiological processes including survival. Motivated by these in vitro findings, we performed in vivo experiments in rodent models of S. mansoni infection. Unexpectedly, Imatinib had no effect on worm burden or egg-production. We found that the blood components serum albumin (SA) and alpha-1 acid glycoprotein (AGP or orosomucoid) negated Imatinib’s deleterious effects on adult S. mansoni and schistosomula (post-infective larvae) in vitro. This negative effect was partially reversed by erythromycin. AGP synthesis can increase as a consequence of inflammatory processes or infection; in addition upon infection AGP levels are 6–8 times higher in mice compared to humans. Therefore, mice and probably other rodents are poor infection models for measuring the effects of Imatinib in vivo. Accordingly, we suggest the routine evaluation of the ability of AGP and SA to block in vitro anti-schistosomal effects of small molecules like Imatinib prior to laborious and expensive animal experiments.
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影响因子：
6.7
作者：
Buro C;Oliveira KC;Lu Z;Leutner S;Beckmann S;Dissous C;Cailliau K;Verjovski-Almeida S;Grevelding CG
通讯作者：
Grevelding CG
DOI：
10.1164/rccm.200702-178oc
发表时间：
2007-12-15
影响因子：
24.7
作者：
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通讯作者：
Sone, Saburo
影响因子：
8.1
作者：
Chen MG
通讯作者：
Chen MG
影响因子：
3.8
作者：
Buro C;Beckmann S;Oliveira KC;Dissous C;Cailliau K;Marhöfer RJ;Selzer PM;Verjovski-Almeida S;Grevelding CG
通讯作者：
Grevelding CG
影响因子：
13.5
作者：
Fabbro, D;Ruetz, S;Manley, PW
通讯作者：
Manley, PW