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Nitroxoline shows antimyeloma activity by targeting the TRIM25/p53 axle

Mao, Hongwu; Du, Yanyun; Zhang, Zubin; Cao, Biyin; Zhao, Jun; Zhou, Haibin; Mao, Xinliang

doi: 10.1097/CAD.0000000000000466
PRECLINICAL REPORTS
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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.

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

* Hongwu Mao and Yanyun Du contributed equally to the study of this article.

Correspondence to Haibin Zhou, MD, PhD, Department of Orthopedics, The Second Affiliated Hospital, Soochow University, Suzhou 215004, PR China Tel: +86 512 68282030; fax: +86 512 68284303; e-mail: 13913133393@163.com

Correspondence to Xinliang Mao, PhD, MD, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou 215123, PR China Tel/fax: +86 512 658 82152; e-mail: xinliangmao@suda.edu.cn

Received August 31, 2016

Accepted December 1, 2016

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