Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia.
Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia.
复制标题
DOI：
10.18632/oncotarget.10541
复制
发表时间：
2016-08-09
期刊：
影响因子：
--
通讯作者：
Arbiser JL
中科院分区：
文献类型：
--
作者：
Laidlaw KM;Berhan S;Liu S;Silvestri G;Holyoake TL;Frank DA;Aggarwal B;Bonner MY;Perrotti D;Jørgensen HG;Arbiser JL
包括尼洛替尼在内的酪氨酸激酶抑制剂 (TKI) 的使用彻底改变了慢性粒细胞白血病 (CML) 的治疗。然而，目前未满足的临床需求包括在长期 TKI 治疗后对抗持续性白血病干细胞中额外的生存信号通路的激活。包括 CML 在内的癌症中普遍存在的信号改变是活性氧 (ROS) 信号的激活，这可能会增强干细胞活性并介导对传统化疗和靶向抑制剂的耐药性。我们开发了一种新型烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶抑制剂——丙咪嗪蓝 (IB)，其目标是 ROS 生成。已知 CML 中的 ROS 水平相对于正常造血干/祖细胞有所升高，并且不能通过 TKI 来纠正。我们证明，IB 与尼洛替尼一起在抑制 TKI 不敏感的静态 CD34+ CML 慢性期 (CP) 细胞的增殖、活力和克隆形成功能方面具有附加益处，而正常 CD34+ 细胞在体外对这种联合疗法的反应中保留了其克隆形成能力。从机制上讲，IB 的促凋亡活性可能部分归因于其阻断 NF-κB 和重新激活肿瘤抑制蛋白磷酸酶 2A (PP2A) 的双重能力。将 BCR-ABL1 激酶抑制与 NADPH 氧化酶阻断相结合可能有利于根除 CML，值得进一步研究。
The use of tyrosine kinase inhibitors (TKI), including nilotinib, has revolutionized the treatment of chronic myeloid leukemia (CML). However current unmet clinical needs include combating activation of additional survival signaling pathways in persistent leukemia stem cells after long-term TKI therapy. A ubiquitous signaling alteration in cancer, including CML, is activation of reactive oxygen species (ROS) signaling, which may potentiate stem cell activity and mediate resistance to both conventional chemotherapy and targeted inhibitors. We have developed a novel nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, imipramine blue (IB) that targets ROS generation. ROS levels are known to be elevated in CML with respect to normal hematopoietic stem/progenitor cells and not corrected by TKI. We demonstrate that IB has additive benefit with nilotinib in inhibiting proliferation, viability, and clonogenic function of TKI-insensitive quiescent CD34+ CML chronic phase (CP) cells while normal CD34+ cells retained their clonogenic capacity in response to this combination therapy in vitro. Mechanistically, the pro-apoptotic activity of IB likely resides in part through its dual ability to block NF-κB and re-activate the tumor suppressor protein phosphatase 2A (PP2A). Combining BCR-ABL1 kinase inhibition with NADPH oxidase blockade may be beneficial in eradication of CML and worthy of further investigation.