The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling
The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling
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DOI：
10.1158/1535-7163.mct-06-0071
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发表时间：
2006-10-01
影响因子：
5.7
通讯作者：
Taguchi, Hirokuni
中科院分区：
文献类型：
--
作者：
Ikezoe, Takayuki;Nishioka, Chie;Taguchi, Hirokuni
我们研究了受体酪氨酸激酶抑制剂舒尼替尼（原SU11248）对多种血液系统恶性肿瘤的抗肿瘤作用，包括以下白血病：嗜酸性粒细胞（EOL-1），急性髓细胞（THP-1, U937, Kasumi-1），双表型（MV4-11），急性淋巴细胞（NALL-1, Jurkat, BALL-2, PALL-1, PALL-2），慢性髓细胞（KU812, KcI-22, K562），成人t细胞（MT-1, MT-2, MT-4），以及非霍奇金淋巴瘤（KS-1, Dauji, Akata）和多发性骨髓瘤（U266）。胸苷摄取研究表明，舒尼替尼对PDGFR α、FLT-3和c-KIT基因激活突变的EOL-1、MV4-11和Kasumi-1细胞有活性，IC50S < 30 nmol/L。此外，舒尼替尼抑制了FLT3基因突变患者新分离的白血病细胞的增殖。膜联蛋白V染色显示舒尼替尼诱导这些细胞凋亡。舒尼替尼分别抑制FLT3和PDGFR α的磷酸化，同时阻断哺乳动物MV4-11和ehl -1细胞中的雷帕霉素信号靶点。有趣的是，雷帕霉素类似物RAD001增强了舒尼替尼抑制白血病细胞增殖的能力，并下调了雷帕霉素效应物p70 S6激酶和真核起始因子4e结合蛋白1在这些细胞中的靶蛋白水平。综上所述，舒尼替尼可能对具有酪氨酸激酶活化突变的白血病患者有用，舒尼替尼和RAD001的联合治疗代表了一种有前景的新治疗策略。
We studied antitumor effects of receptor tyrosine kinase inhibitor sunitinib (formerly SU11248) against a variety of hematologic malignancies including the following leukemias: eosinophilic (EOL-1), acute myeloid (THP-1, U937, Kasumi-1), biphenotypic (MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, PALL-2), blast crisis of chronic myeloid (KU812, KcI-22, K562), and adult T-cell (MT-1, MT-2, MT-4), as well as non-Hodgkin's lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine uptake studies showed that sunitinib was active against EOL-1, MV4-11, and Kasumi-1 cells, which possessed activating mutations of the PDGFR alpha, FLT-3, and c-KIT genes, respectively, with IC50S of < 30 nmol/L. In addition, sunitinib inhibited the proliferation of freshly isolated leukemia cells from patients possessing mutations in FLT3 gene. Annexin V staining showed that sunitinib induced apoptosis of these cells. Sunitinib inhibited phosphorylation of FLT3 and PDGFR alpha in conjunction with blockade of mammalian target of rapamycin signaling in MV4-11 and EOL-1 cells, respectively. Interestingly, rapamycin analogue RAD001 enhanced the ability of sunitinib to inhibit the proliferation of leukemia cells and down-regulate levels of mammalian target of rapamycin effectors p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in these cells. Taken together, sunitinib may be useful for treatment of individuals with leukemias possessing activation mutation of tyrosine kinase, and the combination of sunitinib and RAD001 represents a promising novel treatment strategy.