Repositioning CEP-1347, a chemical agent originally developed for the treatment of Parkinson's disease, as an anti-cancer stem cell drug.
Repositioning CEP-1347, a chemical agent originally developed for the treatment of Parkinson's disease, as an anti-cancer stem cell drug.
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DOI：
10.18632/oncotarget.22033
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发表时间：
2017-11-07
期刊：
影响因子：
--
通讯作者：
Kitanaka C
中科院分区：
文献类型：
--
作者：
Okada M;Takeda H;Sakaki H;Kuramoto K;Suzuki S;Sanomachi T;Togashi K;Seino S;Kitanaka C
CEP-1347是一种混合谱系激酶抑制剂，在一项针对早期帕金森病的大规模2/3期临床试验中进行了测试，该试验证明了其安全性和耐受性，但没有疗效。在这里，我们通过药物重新定位CEP-1347作为一种潜在的抗癌干细胞药物。在体外实验中，CEP-1347在临床相关浓度下有效诱导分化，抑制来自胶质母细胞瘤、胰腺癌和卵巢癌的人类癌症干细胞的自我更新和肿瘤启动能力，而不损害正常成纤维细胞和神经干细胞的活力。在体内，10天的CEP-1347全身给药剂量小于人类安全给药剂量的1/10，足以有效减少小鼠已建立肿瘤内的肿瘤启动性癌症干细胞。此外，同样的治疗方案显著延长了接受胶质瘤干细胞原位植入的小鼠的存活时间。总之，我们的研究结果表明，CEP-1347是癌症干细胞靶向治疗的有希望的候选者，需要进一步的临床和临床前研究来评估其在癌症治疗中的疗效。
CEP-1347 is a mixed lineage kinase inhibitor tested in a large-scale phase 2/3 clinical trial in early Parkinson’s disease, in which its safety and tolerability, but nevertheless not efficacy, was demonstrated. Here we identify by drug repositioning CEP-1347 as a potential anti-cancer stem cell drug. In vitro, CEP-1347 efficiently induced differentiation and inhibited the self-renewal and tumor-initiating capacities of human cancer stem cells from glioblastoma as well as from pancreatic and ovarian cancers at clinically-relevant concentrations, without impairing the viability of normal fibroblasts and neural stem cells. In vivo, a 10-day systemic administration of CEP-1347 at a dose that was less than 1/10 the mouse equivalent of the dose safely given to humans for 2 years was sufficient to effectively reduce tumor-initiating cancer stem cells within established tumors in mice. Furthermore, the same treatment protocol significantly extended the survival of mice receiving orthotopic implantation of glioma stem cells. Together, our findings suggest that CEP-1347 is a promising candidate for cancer stem cell-targeting therapy and that further clinical and preclinical studies are warranted to evaluate its efficacy in cancer treatment.
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影响因子：
--
作者：
Okada M;Kuramoto K;Takeda H;Watarai H;Sakaki H;Seino S;Seino M;Suzuki S;Kitanaka C
通讯作者：
Kitanaka C
影响因子：
7.3
作者：
Goodfellow VS;Loweth CJ;Ravula SB;Wiemann T;Nguyen T;Xu Y;Todd DE;Sheppard D;Pollack S;Polesskaya O;Marker DF;Dewhurst S;Gelbard HA
通讯作者：
Gelbard HA
CEP-1347在神经辅助模型中的神经保护活性。
DOI：
10.4049/jimmunol.0902962
发表时间：
2010-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Eggert D;Dash PK;Gorantla S;Dou H;Schifitto G;Maggirwar SB;Dewhurst S;Poluektova L;Gelbard HA;Gendelman HE
通讯作者：
Gendelman HE
影响因子：
3.2
作者：
Ma, Qing;Gelbard, Harris A.;Schifitto, Giovanni
通讯作者：
Schifitto, Giovanni
影响因子：
4.8
作者：
Roux, PP;Dorval, G;Barker, PA
通讯作者：
Barker, PA