Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-κB and mTOR dual-targeting approach.
Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-κB and mTOR dual-targeting approach.
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DOI：
10.1158/1535-7163.mct-13-0239
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发表时间：
2013-10
影响因子：
5.7
通讯作者：
Joshi SS
中科院分区：
文献类型：
--
作者：
Chaturvedi NK;Rajule RN;Shukla A;Radhakrishnan P;Todd GL;Natarajan A;Vose JM;Joshi SS
套细胞淋巴瘤(MCL)是最具侵袭性的B细胞性非霍奇金淋巴瘤之一，中位生存期约5年。目前，由于耐药肿瘤细胞复发，难治性MCL尚无根治性治疗方法。在难治性MCL中，NF-κB和mTOR通路在结构性上是活跃的，导致增殖和生存的增加。靶向这些通路是改善难治性MCL治疗的理想策略。因此，我们研究了一种新的化合物13-197的体外和体内抗淋巴瘤活性及其相关的分子作用机制。13-197是一种喹恶啉类似物，特异性干扰IκB激酶(IKK)β，IκB途径的关键调节因子。与对照组相比，13-197抑制包括耐药细胞在内的MCL细胞的增殖和诱导其凋亡。此外，我们观察到13-197下调了MCL细胞中I-κBα的磷酸化，抑制了核转录因子-κB的核转位。此外，NF-κB调控基因Cyclin D1、Bclxl和Mcl-1在13-197处理的细胞中表达下调。13-197还抑制mTOR通路下游分子S6K和4E-BP1的磷酸化，这两个分子在难治性MCL中也被激活。此外，与赋形剂治疗的小鼠相比，13-197降低了耐药的MCL荷瘤NOD-SCID小鼠肾脏、肝脏和肺部的体内肿瘤负担；实际上，13-197显著提高了MCL移植小鼠的存活率。综上所述，结果表明，13-197作为单一药物扰乱了NF-κB和mTOR通路，从而抑制了恶性MCL细胞的增殖和增加了细胞凋亡，包括减轻了小鼠的肿瘤负担。
Mantle cell lymphoma (MCL) is one of the most aggressive B cell non-Hodgkin lymphomas with a median survival of about five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB and mTOR pathways are constitutively active in refractory MCL leading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis in MCL cells including therapy-resistant cells compared to control cells. Furthermore, we observed down-regulation of IκBα phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB regulated genes such as cyclin D1, Bcl-XL and Mcl-1 were down-regulated in 13-197-treated cells. 13-197 also inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL bearing NOD-SCID mice compared to vehicle treated mice; indeed, 13-197 significantly increased the survival of MCL transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading suppression of proliferation and increased apoptosis in malignant MCL cells including reduction in tumor burden in mice.