A novel histone acetyltransferase inhibitor A485 improves sensitivity of non-small-cell lung carcinoma cells to TRAIL.

Abstract

Transcriptional coactivators p300 and CBP catalyze the acetylation of lysine residues in histone proteins. Upregulation of p300 and CBP has been associated with lung, colorectal and hepatocellular cancer, indicating an important role of p300 and CBP in tumorigenesis. Recently, the novel p300 and CBP-selective inhibitor A485 became available, which was shown to inhibit proliferation of 124 different cancer cell lines. Here, we found that downregulation of EP300 or CREBBP enhances apoptosis upon TRAIL stimulation in non-small-cell lung cancer (NSCLC) cells. A485 upregulates pro- and anti-apoptotic genes at the mRNA level, implying an apoptosis-modulating effect in NSCLC cells. However, A485 alone does not induce apoptosis. Interestingly, we observed that the number of apoptotic cells increases upon combined treatment with A485 and TRAIL. Therefore, A485, as a TRAIL-sensitizer, was used in combination with TRAIL in wild type of NSCLC cell lines (HCC827 and H1650) and cells with acquired erlotinib resistance (HCC827-ER and H1650-ER). Our results show that the combination of A485 and TRAIL synergistically increases cell death and inhibits long-term cell proliferation. Furthermore, this combination inhibits the growth of 3D spheroids of EGFR-TKI-resistant cells. Taken together, we demonstrate a successful combination of A485 and TRAIL in EGFR-TKI-sensitive and resistant NSCLC cells.

• Authors: Baojie Zhang, Deng Chen, Bin Liu, Frank J Dekker, Wim J Quax
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 175 Pg. 113914 (05 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32173363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Histone Acetyltransferases

Topics

• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology)
• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects, physiology)
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Histone Acetyltransferases (antagonists & inhibitors, metabolism)
• Humans
• Lung Neoplasms (drug therapy, enzymology)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, metabolism)