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.

journal_name

Anticancer Drugs

journal_title

Anti-cancer drugs

authors

Mao H,Du Y,Zhang Z,Cao B,Zhao J,Zhou H,Mao X

doi

10.1097/CAD.0000000000000466

subject

Has Abstract

pub_date

2017-04-01 00:00:00

pages

376-383

issue

4

eissn

0959-4973

issn

1473-5741

pii

00001813-201704000-00004

journal_volume

28

pub_type

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