The NF-κB pathway blockade by the IKK inhibitor PS1145 can overcome Imatinib resistance

被引:81
作者
Cilloni, D
Messa, F
Arruga, F
Defilippi, I
Morotti, A
Messa, E
Carturan, S
Giugliano, E
Pautasso, M
Bracco, E
Rosso, V
Sen, A
Martinelli, G
Baccarani, M
Saglio, G
机构
[1] Univ Turin, Div Hematol & Internal Med, Dept Clin & Biol Sci, I-10043 Turin, Italy
[2] Univ Turin, Sect Cell Biol, Dept Clin & Biol Sci, I-10124 Turin, Italy
[3] Millennium Pharmaceut Inc, Cambridge, MA USA
[4] Univ Bologna, Inst Hematol & Med Oncol L & A Seragnoli, I-40126 Bologna, Italy
关键词
CML; NF-kappa B; PS1145; Imatinib;
D O I
10.1038/sj.leu.2403998
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-kappa B/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Relblocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-kappa B activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.
引用
收藏
页码:61 / 67
页数:7
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