GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases.
GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases.
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DOI：
10.1002/jcp.25014
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发表时间：
2015-10
影响因子：
5.6
通讯作者：
Dent P
中科院分区：
文献类型：
--
作者：
Roberts JL;Tavallai M;Nourbakhsh A;Fidanza A;Cruz-Luna T;Smith E;Siembida P;Plamondon P;Cycon KA;Doern CD;Booth L;Dent P
先前的肿瘤细胞研究表明，药物索拉非尼(Nexavar)和瑞格拉非尼(Stivarga)减少伴侣GRP78的表达。索拉非尼/雷戈拉非尼和多激酶抑制剂帕佐帕尼(Votrient)与西地那非(伟哥)相互作用，进一步快速降低真核细胞中GRP78的水平，并作为单一药物降低原核生物中的DNA K水平。在体外和药物处理的小鼠肿瘤细胞中也获得了类似的数据：HSP70、线粒体HSP70、HSP60、HSP56、HSP40、HSP10和亲环素A。延长雷非尼/西地那非治疗可杀死肿瘤细胞，并迅速减少药物外排泵ABCB1和ABCG2；以及分别针对埃博拉/肝炎病毒和乙肝病毒的受体NPC1和NTCP的表达。拉非尼布/西地那非联合用药可减少柯萨奇病毒和腺病毒受体的表达，同时也降低了血清5型腺病毒或柯萨奇病毒B4感染和繁殖的能力。索拉非尼/帕佐帕尼和西地那非作为单独用药在防止腺病毒、腮腺炎、基孔肯雅、登革热、狂犬病、西尼罗河病毒、黄热病和肠道病毒71型感染和繁殖方面比索拉非尼/帕佐帕尼更有效。拉非尼药物/帕佐帕尼作为单一药物在实验室杀死了产生抗生素耐药性的大肠杆菌，这与DNA K和Rec A的表达减少有关。轻微毒性剂量的拉菲尼药物/帕佐帕尼恢复了泛抗生素耐药细菌的抗生素敏感性，包括多株肺炎克雷伯菌。因此，DNA K是索拉非尼的抗生素靶点，抑制GRP78/DNA K对癌症以及细菌和病毒感染具有治疗作用。J.细胞。物理。2015年，230：2552-2578。©2015作者。《细胞生理学杂志》由威利期刊出版公司出版。
Prior tumor cell studies have shown that the drugs sorafenib (Nexavar) and regorafenib (Stivarga) reduce expression of the chaperone GRP78. Sorafenib/regorafenib and the multi‐kinase inhibitor pazopanib (Votrient) interacted with sildenafil (Viagra) to further rapidly reduce GRP78 levels in eukaryotes and as single agents to reduce Dna K levels in prokaryotes. Similar data were obtained in tumor cells in vitro and in drug‐treated mice for: HSP70, mitochondrial HSP70, HSP60, HSP56, HSP40, HSP10, and cyclophilin A. Prolonged ‘rafenib/sildenafil treatment killed tumor cells and also rapidly decreased the expression of: the drug efflux pumps ABCB1 and ABCG2; and NPC1 and NTCP, receptors for Ebola/Hepatitis A and B viruses, respectively. Pre‐treatment with the ‘Rafenib/sildenafil combination reduced expression of the Coxsackie and Adenovirus receptor in parallel with it also reducing the ability of a serotype 5 Adenovirus or Coxsackie virus B4 to infect and to reproduce. Sorafenib/pazopanib and sildenafil was much more potent than sorafenib/pazopanib as single agents at preventing Adenovirus, Mumps, Chikungunya, Dengue, Rabies, West Nile, Yellow Fever, and Enterovirus 71 infection and reproduction. ‘Rafenib drugs/pazopanib as single agents killed laboratory generated antibiotic resistant E. coli which was associated with reduced Dna K and Rec A expression. Marginally toxic doses of ‘Rafenib drugs/pazopanib restored antibiotic sensitivity in pan‐antibiotic resistant bacteria including multiple strains of bla kpc Klebsiella pneumoniae. Thus, Dna K is an antibiotic target for sorafenib, and inhibition of GRP78/Dna K has therapeutic utility for cancer and for bacterial and viral infections. J. Cell. Physiol. 230: 2552–2578, 2015. © 2015 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.