Inhibition of related JAK/STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm
Inhibition of related JAK/STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm
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DOI：
10.1111/bjh.12308
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发表时间：
2013-06-01
影响因子：
6.5
通讯作者：
Martinez-Lopez, Joaquin
中科院分区：
文献类型：
--
作者：
Barrio, Santiago;Gallardo, Miguel;Martinez-Lopez, Joaquin
这项研究旨在评估鲁索利替尼与索拉非尼、KNK437、达沙替尼和周福辛在费城阴性慢性骨髓增殖性肿瘤(MPN)中的抗肿瘤作用、分子作用机制和潜在的协同作用。测定了不同化合物对JAK2 V617F阳性细胞系HEL和BA/F3 JAK2V617F EPOR的细胞毒作用和对19例MPN患者骨髓CD34阳性细胞的杀伤作用。Ruxolitinib[IC50pv=15nmo1/L]、索拉非尼(IC50pv=8moL/L)、KNK437(IC50pv=100moL/L)和Perifosine(IC50pv=15moL/L)均能抑制MPN细胞模型和原代细胞的增殖。达沙替尼、KNK437、索拉非尼与鲁索利替尼联用显示出较强的协同作用[联合指数(CI)PV
This study aimed to assess the antitumour effects, molecular mechanisms of action, and potential synergy of ruxolitinib with sorafenib, KNK437, dasatinib, and perifosine, in Philadelphia-negative chronic myeloproliferative neoplasms (MPN). Cytotoxic and cytostatic effects of the different compounds were determined in the JAK2 V617F-positive cell lines, HEL and Ba/F3 JAK2V617F EPOR, and in primary mononuclear and bone marrow CD34-positive cells from 19 MPN patients. Ruxolitinib [50% inhibitory concentration (IC50)PV=15nmol/l], as well as sorafenib (IC50 PV=8mol/l), KNK437 (IC50 PV=100mol/l ), and perifosine (IC50 PV=15mol/l ), were able to inhibit proliferation in cell line models and in primary cells from MPN patients. Dasatinib, KNK437, and sorafenib showed a strong synergistic effect in combination with ruxolitinib [combination index (CI)PV