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.

中文翻译：

---

CUDC-907 通过抑制 HDAC6 下调 c-Myc 表达，在体外和体内表现出针对人胰腺腺癌的有效抗肿瘤活性。


胰腺癌是一种高度恶性的癌症，通常涉及 c-Myc 的失调。研究表明，c-Myc 在多种生理过程的调节中发挥着关键作用，并参与早期肿瘤的发展，导致进展缓慢。因此，抑制 c-Myc 过度表达是胰腺癌治疗的潜在策略。 CUDC-907 是一种新型的磷酸肌醇 3-激酶 (PI3K) 和组蛋白脱乙酰酶 (HDAC) 双重作用抑制剂。它已显示出对淋巴瘤、多发性骨髓瘤或甲状腺癌以及 c-Myc 改变的实体瘤患者的潜在功效，但缺乏关于 CUDC-907 如何调节 c-Myc 的证据。在这项研究中，我们研究了 CUDC-907 在体外和体内对人胰腺癌细胞的影响。我们的结果表明，CUDC-907 在体外有效抑制 9 种胰腺癌细胞系的增殖，IC50 值范围为 6.7 至 54.5 nM。此外，我们还揭示了 CUDC-907 在 Aspc-1、PANC-1 和 Capan-1 胰腺癌细胞中的抗肿瘤机制：它抑制 HDAC6 亚基，从而下调 c-Myc 蛋白水平，这是一种与现有机制。一致地，在人胰腺癌 Aspc-1 异种移植裸鼠体内模型中观察到 CUDC-907 具有非凡的抗肿瘤活性，同时下调肿瘤组织中的 c-Myc 和 Ki67 表达。我们的结果表明 CUDC-907 可以成为治疗胰腺腺癌的有价值的治疗选择。