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

Abstract

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.

• Authors: Xu-Hong Fu, Xiong Zhang, Hong Yang, Xiao-Wei Xu, Zong-Long Hu, Juan Yan, Xing-Ling Zheng, Rong-Rui Wei, Zhu-Qing Zhang, Shi-Rui Tang, Mei-Yu Geng, Xun Huang
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 40 Issue 5 Pg. 677-688 (May 2019) ISSN: 1745-7254 [Electronic] United States
• PMID: 30224636 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• CUDC-907
• Histone Deacetylase Inhibitors
• Ki-67 Antigen
• MKI67 protein, human
• MYC protein, human
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-myc
• Pyrimidines
• HDAC6 protein, human
• Histone Deacetylase 6

Topics

• Adenocarcinoma (drug therapy)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Histone Deacetylase 6 (antagonists & inhibitors)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Humans
• Ki-67 Antigen (metabolism)
• Male
• Mice, Inbred BALB C
• Morpholines (pharmacology, therapeutic use)
• Pancreatic Neoplasms (drug therapy)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-myc (metabolism)
• Pyrimidines (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays