Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia
Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia
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DOI：
10.1038/sj.leu.2405017
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发表时间：
2008-02-01
期刊：
影响因子：
11.4
通讯作者：
Niitsu, Y.
中科院分区：
文献类型：
--
作者：
Matsunaga, T.;Fukai, F.;Niitsu, Y.
我们研究了FNIII14，一种源于纤维连接蛋白(FN)的22肽，能有效地削弱FN与β1-整合素的相互作用，是否能克服急性髓系白血病(AML)中很晚抗原(VLA)-4-FN相互作用诱导的细胞黏附介导的耐药(CAM-DR)。两个AML细胞系U937细胞和HL-60细胞以及6个高表达α4整合素的AML患者的新鲜白血病细胞通过VLA-4到FN的相互作用表现出对阿糖胞苷(Ara C)的CAM-DR，而来自2个A4整合素低表达的AML患者的新鲜白血病细胞不显示CAM-DR到Ara C。在这些CAM-DR白血病细胞中，FNIII14抑制通过粘着斑激酶/Akt信号通路在VLA-4与FN相互作用中诱导的Bcl2上调。在骨髓微小残留病(MRD)小鼠模型中，FNIII14与Ara C联合使用可获得100%的存活率，而Ara C单独使用只能轻微延长存活时间。在小鼠实验中，FNIII14不能增强Ara-C诱导的骨髓抑制作用。因此，抗癌药物和FNIII14的结合有望在化疗后根除骨髓中的MRD。
We investigated whether FNIII14, a 22-mer peptide derived from fibronectin (FN) that potently impairs interaction of FN with beta 1-integrin, could overcome cell adhesion-mediated drug resistance (CAM-DR) induced by very late antigen (VLA)-4-to-FN interaction in acute myelogenous leukemia (AML). Two AML cell lines, U937 cells and HL-60 cells, and fresh leukemic cells from six AML patients with high alpha 4-integrin expression exhibited CAM-DR to cytosine arabinoside (Ara C) through VLA-4-to-FN interaction, while fresh leukemic cells from two AML patients with low a4-integrin expression did not display CAM-DR to Ara C. FNIII14 impaired VLA-4-to-FN interaction and restored sensitivity to Ara C in the CAM-DR leukemic cells. In these CAM-DR leukemic cells, upregulation of Bcl-2, which was induced through the focal adhesion kinase/Akt signal pathway upon VLA-4-to-FN interaction, was inhibited by FNIII14 treatment. In a mouse model of minimal residual disease (MRD) in bone marrow, 100% survival was achieved by combining FNIII14 with Ara C, whereas Ara C alone prolonged survival only slightly. The myelosuppression induced by Ara C was not augmented by the combination of FNIII14 in mouse experiments. Thus, the combination of anticancer drugs and FNIII14 holds promise to eradicate MRD in bone marrow after chemotherapy.