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CUDC-907 displays potent antitumor activity against human pancreatic adenocarcinoma in vitro and in vivo through inhibition of HDAC6 to downregulate c-Myc expression.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-09-17 , DOI: 10.1038/s41401-018-0108-5
Xu-Hong Fu 1, 2 , Xiong Zhang 2 , Hong Yang 2 , Xiao-Wei Xu 2 , Zong-Long Hu 2 , Juan Yan 2 , Xing-Ling Zheng 2 , Rong-Rui Wei 2 , Zhu-Qing Zhang 2 , Shi-Rui Tang , Mei-Yu Geng 2 , Xun Huang 2
Affiliation  

Pancreatic adenocarcinoma is a highly malignant cancer that often involves a deregulation of c-Myc. It has been shown that c-Myc plays a pivotal role in the regulation of a variety of physiological processes and is involved in early neoplastic development, resulting in poor progression. Hence, suppression of c-Myc overexpression is a potential strategy for pancreatic cancer therapy. CUDC-907 is a novel dual-acting inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC). It has shown potential efficiency in patients with lymphoma, multiple myeloma, or thyroid cancer, as well as in solid tumors with c-Myc alterations, but the evidence is lacking for how CUDC-907 regulates c-Myc. In this study, we investigated the effect of CUDC-907 on human pancreatic cancer cells in vitro and in vivo. Our results showed that CUDC-907 potently inhibited the proliferation of 9 pancreatic cancer cell lines in vitro with IC50 values ranging from 6.7 to 54.5 nM. Furthermore, we revealed the antitumor mechanism of CUDC-907 in Aspc-1, PANC-1, and Capan-1 pancreatic cancer cells: it suppressed the HDAC6 subunit, thus downregulating c-Myc protein levels, which was a mode of action distinct from the existing mechanisms. Consistently, the extraordinary antitumor activity of CUDC-907 accompanied by downregulation of c-Myc and Ki67 expression in tumor tissue was observed in a human pancreatic cancer Aspc-1 xenograft nude mouse model in vivo. Our results suggest that CUDC-907 can be a valuable therapeutic option for treating pancreatic adenocarcinoma.

中文翻译:


CUDC-907 通过抑制 HDAC6 下调 c-Myc 表达,在体外和体内表现出针对人胰腺腺癌的有效抗肿瘤活性。



胰腺癌是一种高度恶性的癌症,通常涉及 c-Myc 的失调。研究表明,c-Myc 在多种生理过程的调节中发挥着关键作用,并参与早期肿瘤的发展,导致进展缓慢。因此,抑制 c-Myc 过度表达是胰腺癌治疗的潜在策略。 CUDC-907 是一种新型的磷酸肌醇 3-激酶 (PI3K) 和组蛋白脱乙酰酶 (HDAC) 双重作用抑制剂。它已显示出对淋巴瘤、多发性骨髓瘤或甲状腺癌以及 c-Myc 改变的实体瘤患者的潜在功效,但缺乏关于 CUDC-907 如何调节 c-Myc 的证据。在这项研究中,我们研究了 CUDC-907 在体外和体内对人胰腺癌细胞的影响。我们的结果表明,CUDC-907 在体外有效抑制 9 种胰腺癌细胞系的增殖,IC50 值范围为 6.7 至 54.5 nM。此外,我们还揭示了 CUDC-907 在 Aspc-1、PANC-1 和 Capan-1 胰腺癌细胞中的抗肿瘤机制:它抑制 HDAC6 亚基,从而下调 c-Myc 蛋白水平,这是一种与现有机制。一致地,在人胰腺癌 Aspc-1 异种移植裸鼠体内模型中观察到 CUDC-907 具有非凡的抗肿瘤活性,同时下调肿瘤组织中的 c-Myc 和 Ki67 表达。我们的结果表明 CUDC-907 可以成为治疗胰腺腺癌的有价值的治疗选择。
更新日期:2019-01-26
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