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
Xu-Hong FuXun Huang

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, ...Continue Reading

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Citations

Sep 13, 2019·Science Translational Medicine·Ann LinJason M Sheltzer
Aug 9, 2019·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Brittany L Allen-Petersen, Rosalie C Sears
Oct 2, 2020·The Journal of Clinical Endocrinology and Metabolism·Dongyun ZhangAnthony P Heaney
Nov 16, 2020·Seminars in Cancer Biology·Bernhard BiersackMichael Höpfner
Jan 4, 2022·Cancer Biology & Therapy·Moein Ala

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Methods Mentioned

BETA
histone acetylation
protein assay
electrophoresis
transfection
PCR
flow cytometry
acetylation
histone
xenografts
xenograft

Software Mentioned

CompuSyn
GraphPad Prism
SoftMax
Image J

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