Targeting NEDD8-activating enzyme is a new approach to treat canine diffuse large B-cell lymphoma.

Abstract

Canine diffuse large B-cell lymphoma (DLBCL), the most common hematologic malignancy of dogs, is associated with poor overall survival. The lack of conventional chemotherapies with sustainable efficacy warrants investigation of novel therapies. Pevonedistat (MLN4924) is a potent and selective small molecule NEDD8-activating enzyme inhibitor. In human activated B-cell-like (ABC) diffuse large B-cell lymphoma, pevonedistat induces lymphoma cell apoptosis, DNA damage and G1 cell cycle arrest by inhibiting the nuclear factor-κB (NF-κB) pathway. Genomic and transcriptomic studies showed that the NF-κB pathway is deregulated in canine DLBCL. Our results showed that pevonedistat treatment significantly reduces the viability of canine DLBCL cells by inducing G1 cell cycle arrest and apoptosis. Pevonedistat treatment inhibits NF-κB pathway activation and downregulates NF-κB target genes in canine DLBCL. Moreover, administration of pevonedistat to mice bearing canine DLBCL xenograft tumours resulted in tumour regression. Our in vivo and in vitro studies provide justification for future clinical application of pevonedistat as a potential new anti-cancer therapy that may benefit both canine and human species.

• Authors: A L F V Assumpção, Z Lu, K W Marlowe, K S Shaffer, X Pan
• Journal: Veterinary and comparative oncology (Vet Comp Oncol) Vol. 16 Issue 4 Pg. 606-615 (Dec 2018) ISSN: 1476-5829 [Electronic] England
• PMID: 30101447 (Publication Type: Journal Article)
• Copyright: © 2018 John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents
• Cyclopentanes
• NEDD8 Protein
• Pyrimidines
• Ubiquitin-Activating Enzymes
• pevonedistat

Topics

• Animals
• Antineoplastic Agents (administration & dosage, therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western (veterinary)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclopentanes (administration & dosage, therapeutic use)
• Dog Diseases (drug therapy, enzymology)
• Dogs
• Dose-Response Relationship, Drug
• Inhibitory Concentration 50
• Lymphoma, Large B-Cell, Diffuse (drug therapy, enzymology, veterinary)
• Mice
• Mice, Inbred NOD
• NEDD8 Protein (antagonists & inhibitors)
• Neoplasm Transplantation (veterinary)
• Pyrimidines (administration & dosage, therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction
• Ubiquitin-Activating Enzymes (antagonists & inhibitors)