BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy.
BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy.
复制标题
DOI：
10.1016/j.tranon.2021.101272
复制
发表时间：
2022-01
影响因子：
5
通讯作者：
Agarwal S
中科院分区：
文献类型：
--
作者：
Chilamakuri R;Rouse DC;Yu Y;Kabir AS;Muth A;Yang J;Lipton JM;Agarwal S
AKT过表达与神经母细胞瘤患者预后不良相关。BX-795抑制PDK 1并消除AKT信号传导通路活化。BX-795在神经母细胞瘤球状体肿瘤模型中表现出强大的疗效。与BX-795的组合协同增强阿霉素抗肿瘤活性。BX-795协同致敏ALK突变的神经母细胞瘤细胞系克唑替尼。高危神经母细胞瘤（NB）由于转移性、耐药疾病和治疗相关毒性的复发而代表了儿科肿瘤学的主要临床挑战。对1235例原发性NB患者数据集的分析显示，随着癌症分期进展，AKT 1和AKT 2基因表达显著增加。此外，AKT 1和AKT 2表达均与NB患者的不良总体生存率呈负相关。AKT 1和AKT 2基因编码AKT，驱动许多癌症（包括NB）中已知的主要致癌细胞信号通路。为了抑制AKT通路，我们重新利用了一种抗病毒抑制剂BX-795，其抑制AKT的上游激活剂PDK 1。BX-795以剂量依赖性方式有效抑制NB细胞增殖和集落生长。BX-795可显著促进NB细胞凋亡，并在有丝分裂期阻断细胞周期进程。此外，BX-795有效抑制NB球状体肿瘤模型中的肿瘤形成和生长。我们进一步通过将BX-795与多柔比星或克唑替尼组合来测试双重治疗方法，并发现与单独使用任何一种药物相比，NB生长具有协同和显著的抑制作用。总体而言，我们的数据表明，BX-795抑制AKT通路以抑制NB生长，并且将BX-795与当前疗法组合是NB的有效且临床上易于处理的治疗方法。
AKT overexpression correlates with poor prognosis in neuroblastoma patients. BX-795 inhibits PDK1 and abrogates the AKT signaling pathway activation. BX-795 demonstrates strong efficacy in neuroblastoma spheroid tumor model. Combination with BX-795 synergistically enhances doxorubicin antitumor activity. BX-795 synergistically sensitized ALK mutated neuroblastoma cell lines to crizotinib. High-risk neuroblastoma (NB) represents a major clinical challenge in pediatric oncology due to relapse of metastatic, drug-resistant disease, and treatment-related toxicities. An analysis of 1235 primary NB patient dataset revealed significant increase in AKT1 and AKT2 gene expression with cancer stage progression. Additionally, Both AKT1 and AKT2 expression inversely correlate with poor overall survival of NB patients. AKT1 and AKT2 genes code for AKT that drive a major oncogenic cell signaling pathway known in many cancers, including NB. To inhibit AKT pathway, we repurposed an antiviral inhibitor BX-795 that inhibits PDK1, an upstream activator of AKT. BX-795 potently inhibits NB cell proliferation and colony growth in a dose-dependent manner. BX-795 significantly enhances apoptosis and blocks cell cycle progression at mitosis phase in NB. Additionally, BX-795 potently inhibits tumor formation and growth in a NB spheroid tumor model. We further tested dual therapeutic approaches by combining BX-795 with either doxorubicin or crizotinib and found synergistic and significant inhibition of NB growth, in contrast to either drug alone. Overall, our data demonstrate that BX-795 inhibits AKT pathway to inhibit NB growth, and combining BX-795 with current therapies is an effective and clinically tractable therapeutic approach for NB.
登录
查看更多内容
影响因子：
5.6
作者：
Huang H
通讯作者：
Huang H
影响因子：
8.8
作者：
Huang H;Gont A;Kee L;Dries R;Pfeifer K;Sharma B;Debruyne DN;Harlow M;Sengupta S;Guan J;Yeung CM;Wang W;Hallberg B;Palmer RH;Irwin MS;George RE
通讯作者：
George RE
影响因子：
3.1
作者：
Chen, Qin;Wang, Ming;Shen, Chengji
通讯作者：
Shen, Chengji
影响因子：
4.8
作者：
Clark, Kristopher;Plater, Lorna;Cohen, Philip
通讯作者：
Cohen, Philip
影响因子：
5.2
作者：
Emmanouilidi A;Falasca M
通讯作者：
Falasca M