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.
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Acknowledgements
This work was supported by the Shanghai Talent Development Funds (No. 201663 to XH), the Open Project of State Key Laboratory of Drug Research (No. SIMM1705KF-10 to HH), and the Youth Innovation Promotion Association CAS (to XH).
Author contributions
XH and MYG designed research; XHF performed research; XHF, XZ, HY, XWX, ZLH, JY, XLZ, RRW, ZQZ. and SRT analyzed the data; XH, XHF, and XZ drafted the manuscript; and XH and MYG supervised the work.
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Fu, Xh., Zhang, X., Yang, H. et al. 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 Pharmacol Sin 40, 677–688 (2019). https://doi.org/10.1038/s41401-018-0108-5
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DOI: https://doi.org/10.1038/s41401-018-0108-5
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