Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin.
Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin.
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Selinexor（KPT-330）在体外和体内具有抗肿瘤甲状腺癌的抗肿瘤活性，并增强对阿霉素的敏感性。
DOI：
10.1038/s41598-017-10325-x
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发表时间：
2017-08-29
影响因子：
4.6
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Garg M;Kanojia D;Mayakonda A;Ganesan TS;Sadhanandhan B;Suresh S;S S;Nagare RP;Said JW;Doan NB;Ding LW;Baloglu E;Shacham S;Kauffman M;Koeffler HP
甲状腺间变性癌（ATC）是最致命的恶性肿瘤之一，没有有效的治疗方法。Exportin-1 （XPO1）是许多肿瘤抑制蛋白核输出的关键介质，在人类癌症中过度表达。在这项研究中，我们在体外和体内检测了selinexor （XPO1抑制剂）对人ATC细胞的治疗潜力。在这里，我们发现XPO1在原代ATC样品和人类ATC细胞系中得到了强有力的表达。shRNA或selinexor沉默XPO1均可通过改变癌相关基因的蛋白表达，显著降低ATC细胞的生长，诱导细胞周期阻滞和凋亡。此外，selinexor显著抑制ATC异种移植瘤的生长。微阵列分析显示，selinexor处理的ATC细胞中DNA复制、细胞周期、细胞周期检查点和TNF通路富集。重要的是，selinexor降低了CAL62和HTH83细胞中AXL和GAS6的水平，抑制了AXL信号下游靶点如AKT和P70S6K的磷酸化。最后，selinexor与阿霉素的联合使用显示了几种ATC细胞增殖的协同减少。这些结果为研究selinexor和阿霉素联合治疗改善ATC患者预后的疗效提供了理论依据。
Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies having no effective treatment. Exportin-1 (XPO1) is the key mediator of nuclear export of many tumor suppressor proteins and is overexpressed in human cancers. In this study, we examined the therapeutic potential of selinexor (XPO1 inhibitor) against human ATC cells both in vitro and in vivo. Here, we showed that XPO1 is robustly expressed in primary ATC samples and human ATC cell lines. Silencing of XPO1 by either shRNA or selinexor significantly reduced cellular growth and induced cell cycle arrest, apoptosis of ATC cells by altering the protein expression of cancer-related genes. Moreover, selinexor significantly inhibited tumor growth of ATC xenografts. Microarray analysis showed enrichment of DNA replication, cell cycle, cell cycle checkpoint and TNF pathways in selinexor treated ATC cells. Importantly, selinexor decreased AXL and GAS6 levels in CAL62 and HTH83 cells and suppressed the phosphorylation of downstream targets of AXL signaling such as AKT and P70S6K. Finally, a combination of selinexor with doxorubicin demonstrated a synergistic decrease in the cellular proliferation of several ATC cells. These results provide a rationale for investigating the efficacy of combining selinexor and doxorubicin therapy to improve the outcome of ATC patients.
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影响因子：
64.5
作者：
Fornerod, M;Ohno, M;Mattaj, IW
通讯作者：
Mattaj, IW
影响因子：
11.2
作者：
Avilla, Elvira;Guarino, Valentina;Melillo, Rosa Marina
通讯作者：
Melillo, Rosa Marina
影响因子：
30.8
作者：
Lin DC;Hao JJ;Nagata Y;Xu L;Shang L;Meng X;Sato Y;Okuno Y;Varela AM;Ding LW;Garg M;Liu LZ;Yang H;Yin D;Shi ZZ;Jiang YY;Gu WY;Gong T;Zhang Y;Xu X;Kalid O;Shacham S;Ogawa S;Wang MR;Koeffler HP
通讯作者：
Koeffler HP
影响因子：
8.8
作者：
Newlands, ES;Rustin, GJS;Brampton, MH
通讯作者：
Brampton, MH
DOI：
10.1073/pnas.96.16.9112
发表时间：
1999-08-03
影响因子：
11.1
作者：
Kudo, N;Matsumori, N;Horinouchi, S
通讯作者：
Horinouchi, S