Assumpção A L F V, Lu Z, Marlowe K W, Shaffer K S, Pan X
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
Vet Comp Oncol. 2018 Dec;16(4):606-615. doi: 10.1111/vco.12428. Epub 2018 Aug 13.
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.
犬弥漫性大B细胞淋巴瘤（DLBCL）是犬最常见的血液系统恶性肿瘤，与总体生存率低相关。缺乏具有可持续疗效的传统化疗方法，因此有必要研究新的治疗方法。pevonedistat（MLN4924）是一种强效且选择性的小分子NEDD8激活酶抑制剂。在人类活化B细胞样（ABC）弥漫性大B细胞淋巴瘤中，pevonedistat通过抑制核因子-κB（NF-κB）途径诱导淋巴瘤细胞凋亡、DNA损伤和G1期细胞周期停滞。基因组和转录组研究表明，NF-κB途径在犬DLBCL中失调。我们的结果表明，pevonedistat治疗通过诱导G1期细胞周期停滞和凋亡显著降低犬DLBCL细胞的活力。pevonedistat治疗可抑制犬DLBCL中NF-κB途径的激活并下调NF-κB靶基因。此外，对携带犬DLBCL异种移植肿瘤的小鼠施用pevonedistat可导致肿瘤消退。我们的体内和体外研究为pevonedistat作为一种潜在的新抗癌疗法的未来临床应用提供了依据，该疗法可能对犬类和人类都有益。
