Anti-tumor effects of dual PI3K-HDAC inhibitor CUDC-907 on activation of ROS-IRE1α-JNK-mediated cytotoxic autophagy in esophageal cancer

Abstract

Background PI3K-Akt pathway activation and the expression of histone deacetylases (HDACs) are highly increased in esophageal cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy. Herein, we aimed to evaluate the anti-tumor effect of CUDC-907, a dual PI3K-HDAC inhibitor, in esophageal squamous cell carcinoma (ESCC). Methods The anti-tumor effects of CUDC-907 in ESCC were evaluated using cell counting kit-8, flow cytometry, and western blot. mRNA-sequencing was used to explore the mechanism underlying CUDC-907 anti-tumor effects. The relations of reactive oxygen species (ROS), lipocalin 2 (LCN2), and CUDC-907 were determined by flow cytometry, rescue experiments, and western blot. The activation of the IRE1α-JNK-CHOP signal cascade was confirmed by western blot. The in vivo inhibitory effects of CUDC-907 were examined by a subcutaneous xenograft model in nude mice. Results CUDC-907 displayed effective inhibition in the proliferation, migration, and invasion of ESCC cells. Through an mRNA-sequencing and functional enrichment analysis, autophagy was found to be associated with cancer cells death. CUDC-907 not only inhibited the PI3K-Akt-mTOR pathways to result in autophagy, but also induced ROS accumulation to activate IRE1α-JNK-CHOP-mediated cytotoxic autophagy by downregulating LCN2 expression. Consistently, the in vivo anti-tumor effects of CUDC-907 accompanied by the downregulated expression of p-mTOR and LCN2 and upregulated expression of p-IRE1α and LC3B-II were evaluated in a xenograft mouse model. Conclusion Our findings suggested the clinical development and administration of CUDC-907 might act as a novel treatment strategy for ESCC. A more in-depth understanding of the anti-tumor effect of CUDC-907 in ESCC will benefit the clinically targeted treatment of ESCC.

Epigenetic modifications in esophageal cancer: An evolving biomarker

“…The dual PI3K-HDAC inhibitor CUDC-907 inhibits the PI3K-AKT-mTOR pathway, leading to the downregulation of LCN2 expression and ultimately to the accumulation of ROS and the activation of cytotoxic autophagy. In addition, consistent antitumor effects have been demonstrated in xenograft mouse models ( Jian et al, 2022 ).…”

Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer

“…The molecule was further taken into phase 1a/1b clinical trials against head and neck squamous cell carcinoma and was found to be well tolerated. Another dual inhibitor CUDC-907 (PI3K/HDAC dual inhibitor) was developed and it was tested against different solid cancers like lung and esophageal cancer, neuroblastoma, and also in T-cell leukemia. − …”

Unraveling the Complexity of Regulated Cell Death in Esophageal Cancer: from Underlying Mechanisms to Targeted Therapeutics

“…A recent study demonstrated that HDACs and the PI3K/Akt/mTOR signaling pathway were highly activated in EC cell lines and ESCC patients. As an innovative artificial small-molecule inhibitor that can suppress both the PI3K/Akt/mTOR signaling pathway and HDACs, CUDC-907 has been reported to activate autophagy in ESCC cells by suppressing the PI3K/Akt/mTOR signaling pathway or LCN2 to induce accumulation of ROS, suggesting a potential targeted therapy option for patients with EC 145 . Moreover, it has been reported that the dual PI3K/mTOR inhibitor BEZ235 enhances antitumor activities by promoting autophagy in ESCC cells through the inhibition of the PI3K/Akt/mTOR signaling pathway 146 .…”