Degrasyn potentiates the antitumor effects of bortezomib in mantle cell lymphoma cells in vitro and in vivo: therapeutic implications.
Degrasyn potentiates the antitumor effects of bortezomib in mantle cell lymphoma cells in vitro and in vivo: therapeutic implications.
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DOI：
10.1158/1535-7163.mct-10-0238
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发表时间：
2010-07
影响因子：
5.7
通讯作者：
Ford RJ
中科院分区：
文献类型：
--
作者：
Pham LV;Tamayo AT;Li C;Bornmann W;Priebe W;Ford RJ
套细胞淋巴瘤（MCL）是B细胞非霍奇金淋巴瘤的一种侵袭性组织型，在过去几十年中发病率增加，并且不可治愈，通常对标准化疗组合反应不良，并且与不良预后相关。发现新的低毒性治疗药物，在MCL患者中产生良好的结果是一个持续的挑战。最近的研究表明，degrasyn，Janus激酶（JAK）/信号转导和转录激活（STAT）通路的一种新型小分子抑制剂，通过抑制关键的生长和存活信号通路在淋巴肿瘤中发挥抗肿瘤活性。在本研究中，我们发现，治疗典型的和类胚细胞变异MCL细胞与degrasyn结合硼替佐米导致协同生长抑制和凋亡诱导体外。这些细胞的凋亡与组成性核因子-κB的下调和磷酸化STAT 3的激活相关，从而抑制c-Myc、细胞周期蛋白D1和bcl-2蛋白的表达并上调Bax蛋白的表达。在MCL异种移植严重联合免疫缺陷小鼠（SCID）模型中，地格拉辛和硼替佐米在体内相互作用，协同预防肿瘤发展并延长生存期。这些发现表明，当与硼替佐米一起给药时，可以靶向MCL细胞中组成型表达的核因子-κB和STAT 3的药物（如degrasyn）可能是MCL的有用治疗药物。
Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that has increased in incidence over the past few decades and is incurable, usually poorly responsive to standard chemotherapy combinations, and associated with poor prognoses. Discovering new therapeutic agents with low toxicity that produce good outcomes in patients with MCL is an ongoing challenge. Recent studies showed that degrasyn, a novel small-molecule inhibitor of the Janus kinase (JAK)/signal transducer and activation of transcription (STAT) pathway, exerts antitumor activity in lymphoid tumors by inhibiting key growth and survival signaling pathways. In the present study, we found that treatment of both typical and blastoid-variant MCL cells with degrasyn in combination with bortezomib resulted in synergistic growth inhibition and apoptosis induction in vitro. The apoptosis in these cells was correlated with down-regulation of constitutive nuclear factor-κB and phosphorylated STAT3 activation, leading to inhibition of c-Myc, cyclin D1, and bcl-2 protein expression and upregulation of bax protein expression. In vivo, degrasyn and bortezomib interacted to synergistically prevent tumor development and prolong survival durations in a xeno-transplant severe combined immunodeficiency mouse (SCID) model of MCL. These findings suggest that agents such as degrasyn that can pharmacologically target constitutively expressed nuclear factor-κB and STAT3 in MCL cells, may be useful therapeutic agents for MCL when administered together with bortezomib.