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

Cited by 27 publications

(22 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MM cells were infected with lentiviral UBE2O for 1 - 7 d before being subjected to MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay as described previously [17, 18]. …”

Section: Methodsmentioning

confidence: 99%

The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis

Zhang

et al. 2017

J Hematol Oncol

Self Cite

View full text Add to dashboard Cite

BackgroundUBE2O is proposed as a ubiquitin-conjugating enzyme, but its function was largely unknown.MethodsMass spectrometry was applied to identify c-Maf ubiquitination-associated proteins. Immunoprecipitation was applied for c-Maf and UBE2O interaction. Immunoblotting was used for Maf protein stability. Luciferase assay was used for c-Maf transcriptional activity. Lentiviral infections were applied for UBE2O function in multiple myeloma (MM) cells. Flow cytometry and nude mice xenografts were applied for MM cell apoptosis and tumor growth assay, respectively.ResultsUBE2O was found to interact with c-Maf, a critical transcription factor in MM, by the affinity purification/tandem mass spectrometry assay and co-immunoprecipitation assays. Subsequent studies showed that UBE2O mediated c-Maf polyubiquitination and degradation. Moreover, UBE2O downregulated the transcriptional activity of c-Maf and the expression of cyclin D2, a typical gene modulated by c-Maf. DNA microarray revealed that UBE2O was expressed in normal bone marrow cells but downregulated in MGUS, smoldering MM and MM cells, which was confirmed by RT-PCR in primary MM cells, suggesting its potential role in myeloma pathophysiology. When UBE2O was restored, c-Maf protein in MM cells was significantly decreased and MM cells underwent apoptosis. Furthermore, the human MM xenograft in nude mice showed that re-expression of UBE2O delayed the growth of myeloma xenografts in nude mice in association with c-Maf downregulation and activation of the apoptotic pathway.ConclusionsUBE2O mediates c-Maf polyubiquitination and degradation, induces MM cell apoptosis, and suppresses myeloma tumor growth, which provides a novel insight in understanding myelomagenesis and UBE2O biology.

show abstract

Section: Methodsmentioning

confidence: 99%

The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis

Zhang

et al. 2017

J Hematol Oncol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, nitroxoline was found to induce apoptosis in multiple myeloma (Mao et al, 2017). Similar to that as in glioma cells, treatment of multiple myeloma cell lines with nitroxoline activated caspase 3 in a concentrationdependent manner and caused cleavage and inactivation of PARP, as well as of deactivated survival proteins such as Bcl-xL and Mcl-1.…”

Section: Antitumor Activity Of Nitroxolinementioning

confidence: 72%

“…Similar to that as in glioma cells, treatment of multiple myeloma cell lines with nitroxoline activated caspase 3 in a concentrationdependent manner and caused cleavage and inactivation of PARP, as well as of deactivated survival proteins such as Bcl-xL and Mcl-1. Additionally, in multiple myeloma, nitroxoline was suggested to affect apoptosis by concentration-dependent downregulation of a triple motif containing 25 (TRIM25)/p53 axle (Mao et al, 2017). The protein encoded by the TRIM25 gene is a member of the tripartite motif (TRIM) family ubiquitin ligases.…”

Section: Antitumor Activity Of Nitroxolinementioning

confidence: 99%

Nitroxoline: repurposing its antimicrobial to antitumor application

Mitrović

Kos

2019

Acta Biochim Pol

View full text Add to dashboard Cite

Cancer is a disease receiving an outstanding input of funds for basic and clinical research but is, nevertheless, still the second leading cause of death in the developed world and a great burden for health systems. New drugs are therefore needed to improve therapy, prolong survival of cancer patients and improve their quality of life. The high cost of development and clinical evaluation of new drugs limits the number that actually enter clinical use. To overcome this problem, repurposing of established drugs for new indications has gained a lot of interest, especially in the field of oncology. The well-established antimicrobial agent nitroxoline has been identified as a promising candidate to be repurposed for cancer treatment in several independent studies. Here we have reviewed a wide range of molecular mechanisms and tumor models involving nitroxoline in impairment of tumor progression. Furthermore, nitroxoline was used as a lead compound for structure-based chemical synthesis of new derivatives in order to improve its potency as well as selectivity for various targets. The potent antitumor activity of nitroxoline points strongly in the direction of its repurposing for cancer treatment and to the benefits of this strategy for patients and healthcare system.

show abstract

“…Nitroxoline, an FDA‐approved antibiotic, was identified to display antitumor activity, which was considered to be repurposed for tumor therapy . A recent study reported that NXQ was screened out to show antimyeloma activity both in vitro and in vivo by targeting the TRIM25/p53 axis . In cholangiocarcinoma cells, NXQ also exhibited anticancer activity by inducing FoxM1 inhibition .…”

Section: Discussionmentioning

confidence: 99%

“…13 A recent study reported that NXQ was screened out to show antimyeloma activity both in vitro and in vivo by targeting the TRIM25/ p53 axis. 14 In cholangiocarcinoma cells, NXQ also exhibited anticancer activity by inducing FoxM1 inhibition. 15 NXQ was also considered as a potent and selective inhibitor of cathepsin B, hence reducing glioma tumor progression in vitro and in vivo, and a number of derivatives of NXQ were developed by using structure-based chemical synthesis in order to further improve its antitumor properties.…”

Section: Discussionmentioning

confidence: 99%

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

Shi

2019

The Kaohsiung J of Med Scie

View full text Add to dashboard Cite

The proto‐oncogene MDM2 is a nuclear‐localized E3 ubiquitin ligase, which promotes tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. In this study, the anti‐infective drug nitroxoline (NXQ) was screened out to effectively inhibit cell survival of small‐cell lung cancer (SCLC) cells, and induce SCLC cell apoptosis by suppressing antiapoptotic proteins (such as Bcl‐2 and MCL1) and upregulating proapoptotic protein Bim. In the mechanistic study, NXQ was found to downregulate MDM2 expression by inducing its proteasomal degradation, and thus upregulated p53 expression, which was a substrate protein of MDM2. Moreover, overexpression of MDM2 decreased the cytotoxicity of NXQ on SCLC cells. These results demonstrated that NXQ displayed anti‐SCLC activity by suppressing MDM2 expression, which suggested that anti‐infective NXQ had potential for SCLC treatment by targeting the MDM2/p53 axis.

show abstract

Nitroxoline shows antimyeloma activity by targeting the TRIM25/p53 axle

Cited by 27 publications

References 39 publications

The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis

The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis

Nitroxoline: repurposing its antimicrobial to antitumor application

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

Contact Info

Product

Resources

About