Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment.
Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment.
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DOI：
10.1038/srep34397
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发表时间：
2016-09-30
影响因子：
4.6
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Li H;Chen Z;Hu T;Wang L;Yu Y;Zhao Y;Sun W;Guan S;Pang JC;Woodfield SE;Liu Q;Yang J
神经母细胞瘤（NB）是儿童最常见的颅外恶性实体瘤，并继续导致许多儿科癌症患者死亡。高风险NB的不良结局主要归因于化疗耐药肿瘤细胞的发展。多柔比星（dox）已被广泛用作化疗方案中的有效抗癌剂;然而，它也导致包括NB在内的许多癌症类型的化学抗性。因此，开发新的小分子，可以克服阿霉素诱导的化疗耐药性是一个有前途的策略，在癌症治疗。在此，我们发现第二代蛋白酶体抑制剂ixazomib（MLN 9708）不仅在体外抑制NB细胞增殖并诱导细胞凋亡，而且在NB细胞中增强dox诱导的细胞毒性。Ixlatin抑制dox诱导的NF-κB活性，并使NB细胞对dox诱导的凋亡敏感。更重要的是，Ixazomib通过增强原位异种移植NB小鼠模型中的dox诱导的细胞凋亡，证明了体内强效抗肿瘤疗效。总的来说，我们的研究说明了ixazomib单独给药和与dox联合给药在NB中的抗肿瘤疗效，表明包括ixazomib与传统治疗药物（如dox）的联合治疗是一种可行的策略，可为NB患者实现更好的结局。
Neuroblastoma (NB) is the most common extracranial malignant solid tumor seen in children and continues to lead to the death of many pediatric cancer patients. The poor outcome in high risk NB is largely attributed to the development of chemoresistant tumor cells. Doxorubicin (dox) has been widely employed as a potent anti-cancer agent in chemotherapeutic regimens; however, it also leads to chemoresistance in many cancer types including NB. Thus, developing novel small molecules that can overcome dox-induced chemoresistance is a promising strategy in cancer therapy. Here we show that the second generation proteasome inhibitor ixazomib (MLN9708) not only inhibits NB cell proliferation and induces apoptosis in vitro but also enhances dox-induced cytotoxicity in NB cells. Ixazomib inhibits dox-induced NF-κB activity and sensitizes NB cells to dox-induced apoptosis. More importantly, ixazomib demonstrated potent anti-tumor efficacy in vivo by enhancing dox-induced apoptosis in an orthotopic xenograft NB mouse model. Collectively, our study illustrates the anti-tumor efficacy of ixazomib in NB both alone and in combination with dox, suggesting that combination therapy including ixazomib with traditional therapeutic agents such as dox is a viable strategy that may achieve better outcomes for NB patients.
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