Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells.
Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells.
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DOI：
10.1371/journal.pone.0077390
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Khosravi-Far R
中科院分区：
文献类型：
--
作者：
Bucur O;Stancu AL;Goganau I;Petrescu SM;Pennarun B;Bertomeu T;Dewar R;Khosravi-Far R
慢性粒细胞白血病（CML）对酪氨酸激酶抑制剂（TKI）（如伊马替尼、达沙替尼和尼洛替尼）的耐药性需要新的治疗策略。我们和其他人之前已经确定硼替佐米（一种选择性蛋白酶体抑制剂）是CML的一种重要潜在治疗方法。在这里，我们表明，硼替佐米与有丝分裂抑制剂，如微管稳定剂Paclitazone和PLK 1抑制剂BI 2536的联合方案，有效地杀死TKIs耐药和敏感的Bcr-Abl阳性白血病细胞。联合治疗激活半胱天冬酶8、9和3，其与半胱天冬酶诱导的PARP裂解相关。这些效应与应激相关的MAP激酶p38 MAPK和JNK的活化显著增加有关。有趣的是，联合治疗诱导总Bcr-Abl蛋白水平和磷酸化Bcr-Abl蛋白水平显著降低，并抑制Bcr-Abl下游的信号传导途径：下调STAT 3和STAT 5磷酸化和/或总水平，并降低Bcr-Abl相关蛋白CrkL和林恩的磷酸化。此外，我们发现，其他有丝分裂抑制剂（阿贝斯汀和多西他赛），与硼替佐米组合，也抑制Bcr-Abl诱导的促生存信号，并导致caspase 3激活。这些结果为Bcr-Abl阳性白血病的治疗开辟了新的可能性，特别是在伊马替尼，达沙替尼和尼洛替尼耐药的CML病例中。
Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr-Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.
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影响因子：
24.3
作者：
Correia, Ana Luisa;Bissell, Mina J.
通讯作者：
Bissell, Mina J.
影响因子：
5.2
作者：
Marech, Ilaria;Vacca, Angelo;Dammacco, Franco
通讯作者：
Dammacco, Franco
影响因子：
2.6
作者：
Myssina, Svetlana;Helgason, G. Vignir;Holyoake, Tessa L.
通讯作者：
Holyoake, Tessa L.
影响因子：
11.2
作者：
Gleixner, Karoline V.;Ferenc, Veronika;Valent, Peter
通讯作者：
Valent, Peter
影响因子：
20.3
作者：
He, YP;Wertheim, JA;Pear, WS
通讯作者：
Pear, WS