Napabucasin, a novel inhibitor of STAT3, inhibits growth and synergises with doxorubicin in diffuse large B-cell lymphoma.

Abstract

Diffuse large B-cell lymphoma (DLBCL), the most common type of aggressive non-Hodgkin lymphoma (NHL), has highly heterogeneous molecular characteristics. Although some patients initially respond to standard R-CHOP therapy, 30-40% develop refractory disease or suffer relapse. Signal transducer and activator of transcription 3 (STAT3), which regulates multiple oncogenic processes, has been found to be constitutively activated in various cancers, including DLBCL, suggesting its potential as a therapeutic target. In this study, we determined that 34% (23/69) of DLBCL patients expressed pSTAT3 (Y705) in tumour tissues. Napabucasin, a novel STAT3 inhibitor, exhibited potent cytotoxicity against NHL cell lines in a dose-dependent manner. Mechanistic studies demonstrated that napabucasin induced intrinsic and extrinsic cell apoptosis, downregulated the expression of STAT3 target genes, including the antiapoptotic protein Mcl-1, and regulated the ROS-mediated mitogen-activated protein kinase (MAPK) pathway. Most importantly, in vivo studies revealed the suppressive efficacy of napabucasin as a monotherapy without obvious toxicity. Furthermore, preliminary combination studies of napabucasin with doxorubicin showed significant synergism both in vitro and in vivo. Thus, our studies provide evidence that napabucasin alone or in combination is a promising therapeutic candidate for DLBCL patients.

• Authors: Xue Li, Yuquan Wei, Xiawei Wei
• Journal: Cancer letters (Cancer Lett) Vol. 491 Pg. 146-161 (10 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 32798587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Benzofurans
• Naphthoquinones
• STAT3 Transcription Factor
• napabucasin
• Doxorubicin
• Caspases

Topics

• Benzofurans (pharmacology)
• Caspases (physiology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Drug Synergism
• Female
• Humans
• Lymphoma, Large B-Cell, Diffuse (drug therapy, pathology)
• MAP Kinase Signaling System (drug effects)
• Naphthoquinones (pharmacology)
• STAT3 Transcription Factor (analysis, antagonists & inhibitors)
• Xenograft Model Antitumor Assays