title: Nitroxoline shows antimyeloma activity by targeting the TRIM25/p53 axle.
abstract: The aim of this study was to identify the most potent quinoline-based anti-infectives for the treatment of multiple myeloma (MM) and to understand the molecular mechanisms. A small-scale screen against a panel of marketed quinoline-based drugs was performed in MM cell lines. Cell apoptosis was examined by flow cytometry. Anti-MM activity was also evaluated in nude mice. Western blotting was performed to investigate mechanisms. Nitroxoline (NXQ) was the most effective in suppressing MM cell proliferation. NXQ induced more than 40% MM cell apoptosis within 24 h and potentiated anti-MM activities of current major drugs including doxorubicin and lenalidomide. This finding was shown by activation of caspase-3, a major executive apoptotic enzyme, and by inactivation of PARP, a major enzyme in DNA damage repair. NXQ also suppressed prosurvival proteins Bcl-xL and Mcl-1. Moreover, NXQ suppressed the growth of myeloma xenografts in nude mice models. In the mechanistic study, NXQ was found to downregulate TRIM25, a highly expressed ubiquitin ligase in MM. Notably, NXQ upregulated tumor suppressor p53, but not PTEN. Furthermore, overexpression of TRIM25 decreased p53 protein. This study indicated that the long-term use of anti-infective NXQ has potential for MM treatment by targeting the TRIM25/p53 axle.
authors.affiliation: aDepartment of Orthopedics, The Second Affiliated Hospital bJiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences cJiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University dDepartment of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, Jiangsu eSchool of Basic Sciences, Guangzhou Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Mao
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Du
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhou
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D000072283:A549 Cells; D000818:Animals; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009600:Nitroquinolines / Q000494:pharmacology*; D056687:Off-Label Use; D011897:Random Allocation; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009600:Nitroquinolines; C495901:TP53 protein, human; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D016159:Tumor Suppressor Protein p53; C005308:nitroxoline; C084523:TRIM25 protein, human; D044767:Ubiquitin-Protein Ligases