Tong Sun1,2, Yujia Xu3, Zhuan Xu2, Biyin Cao3, Zubin Zhang3, Qi Wang4, Yan Kong5, Xinliang Mao6,7,8. 1. Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China. 2. Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, 215100, Jiangsu, People's Republic of China. 3. Department of Pharmacology, Soochow University, Suzhou, 215123, Jiangsu, People's Republic of China. 4. Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China. wangqi@gzucm.edu.cn. 5. Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, 215100, Jiangsu, People's Republic of China. kong0919@163.com. 6. Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China. xinliangmao@gzhmu.edu.cn. 7. Department of Pharmacology, Soochow University, Suzhou, 215123, Jiangsu, People's Republic of China. xinliangmao@gzhmu.edu.cn. 8. Guangdong Institute of Cardiovascular Diseases & Guangdong Key Lab for Protein Modifications and Degradation, The Second Affiliated Hospital & School of Basic Medicine, Guangzhou Medical University , Guangzhou, 511436, People's Republic of China. xinliangmao@gzhmu.edu.cn.
Abstract
BACKGROUND: The oncogenic transcript factor c-Maf is stabilized by the deubiquitinase Otub1 and promotes myeloma cell proliferation and confers to chemoresistance. Inhibition of the Otub1/c-Maf axis is a promising therapeutic target, but there are no inhibitors reported on this specific axis. METHODS: A luciferase assay was applied to screen potential inhibitors of Otub1/c-Maf. Annexin V staining/flow cytometry was applied to evaluate cell apoptosis. Immunoprecipitation was applied to examine protein ubiquitination and interaction. Xenograft models in nude mice were used to evaluate anti-myeloma activity of AVT. RESULTS: Acevaltrate (AVT), isolated from Valeriana glechomifolia, was identified based on a bioactive screen against the Otub1/c-Maf/luciferase system. AVT disrupts the interaction of Otub1/c-Maf thus inhibiting Otub1 activity and leading to c-Maf polyubiquitination and subsequent degradation in proteasomes. Consistently, AVT inhibits c-Maf transcriptional activity and downregulates the expression of its target genes key for myeloma growth and survival. Moreover, AVT displays potent anti-myeloma activity by triggering myeloma cell apoptosis in vitro and impairing myeloma xenograft growth in vivo but presents no marked toxicity. CONCLUSIONS: The natural product AVT inhibits the Otub1/c-Maf axis and displays potent anti-myeloma activity. Given its great safety and efficacy, AVT could be further developed for MM treatment. Video Abstract.
BACKGROUND: The oncogenic transcript factor c-Maf is stabilized by the deubiquitinase Otub1 and promotes myeloma cell proliferation and confers to chemoresistance. Inhibition of the Otub1/c-Maf axis is a promising therapeutic target, but there are no inhibitors reported on this specific axis. METHODS: A luciferase assay was applied to screen potential inhibitors of Otub1/c-Maf. Annexin V staining/flow cytometry was applied to evaluate cell apoptosis. Immunoprecipitation was applied to examine protein ubiquitination and interaction. Xenograft models in nude mice were used to evaluate anti-myeloma activity of AVT. RESULTS: Acevaltrate (AVT), isolated from Valeriana glechomifolia, was identified based on a bioactive screen against the Otub1/c-Maf/luciferase system. AVT disrupts the interaction of Otub1/c-Maf thus inhibiting Otub1 activity and leading to c-Maf polyubiquitination and subsequent degradation in proteasomes. Consistently, AVT inhibits c-Maf transcriptional activity and downregulates the expression of its target genes key for myeloma growth and survival. Moreover, AVT displays potent anti-myeloma activity by triggering myeloma cell apoptosis in vitro and impairing myeloma xenograft growth in vivo but presents no marked toxicity. CONCLUSIONS: The natural product AVT inhibits the Otub1/c-Maf axis and displays potent anti-myeloma activity. Given its great safety and efficacy, AVT could be further developed for MM treatment. Video Abstract.
Authors: Paola Neri; Li Ren; Abdel Kareem Azab; Matthew Brentnall; Kathy Gratton; Alexander C Klimowicz; Charles Lin; Peter Duggan; Pierfrancesco Tassone; Adnan Mansoor; Douglas A Stewart; Lawrence H Boise; Irene M Ghobrial; Nizar J Bahlis Journal: Blood Date: 2011-04-07 Impact factor: 22.113
Authors: Tielle Moraes de Almeida; Gilsane Lino von Poser; Liz Girardi Müller; Paula Reis Pereira; Eduardo Cassel; Rubem Mario Figueiro Vargas; Nilson Junior da Silva Nunes; David Driemeier; Eliane Dallegrave; Stella de Faria Valle; Stela Maris Kuze Rates Journal: Curr Drug Discov Technol Date: 2019
Authors: U Karunarathna; M Kongsema; S Zona; C Gong; E Cabrera; A R Gomes; E P S Man; P Khongkow; J W-H Tsang; U-S Khoo; R H Medema; R Freire; E W-F Lam Journal: Oncogene Date: 2015-07-06 Impact factor: 9.867