CUDC-907 displays potent antitumor activity against human pancreatic adenocarcinoma in vitro and in vivo through inhibition of HDAC6 to downregulate c-Myc expression

• 来源期刊: 中国药理学报（英文版）
• 关键词: pancreatic adenocarcinoma CUDC-907 c-Myc HDAC PI3K
• 年，卷（期）: 2019,（5）
• 页码范围: 677-688
• 页数: 12页
• 语种: 英文

摘要

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 dualacting 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.