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 IC 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.

A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells

“…The PI3K/AKT signaling pathway is commonly activated in many human cancers, including pancreatic cancer, and S473 phosphorylation of AKT is required for the full activation of Akt [ 26 , 27 ]. We determined the inhibitory effects of Amcp on the PI3K/AKT pathway and found that 15 µM of Amcp obviously repressed the phosphorylation of AKT at S473.…”

The role of CUDC‐907, a dual phosphoinositide‐3 kinase and histone deacetylase inhibitor, in inhibiting proliferation of adult T‐cell leukemia

“…The stability of c-Myc protein is also regulated via the PI3K pathway. 37 We found that a reduction in Hsp90 chaperone activity might contribute to the observed anti-ATL effect of CUDC-907. HDAC inhibition can induce Hsp90 hyperacetylation, resulting in the loss of its chaperone function and the consequent degradation of client proteins.…”

“…Besides histones, non-histone proteins including c-Myc, NF-κB, Akt, and Hsp90 are also targets of HDAC. [10][11][12]36,37 The acetylation status of non-histone proteins alters several cellular functions such as translation, activity, localization, stability, 10). They were assayed for DNA binding of AP-1 by EMSA.…”

Histone Deacetylase 6 as a Therapeutic Target in B cell-associated Hematological Malignancies

“…Therefore, c-Myc is a promising target in MM. Studies have shown that HDAC6 can promote c-Myc expression by upregulating the tumor suppressor FOXO1, or deacetylating β-catenin to promote its stability and nuclear translocation ( Li et al., 2008 ; Fu et al., 2019 ). At the same time, knocking down or inhibiting c-Myc in MM reduces HDAC6 expression ( Nawrocki et al., 2008 ).…”