Multipotential use of an old drug, as a new solution for anticancer therapy and multidrug-resistant urinary tract infections
DOI:
https://doi.org/10.12775/JEHS.2023.13.03.024Keywords
nitroxoline, nitroxoline cancer, nitroxoline antibacterial useAbstract
Introduction
Nitroxoline (NTX) is a well-known chemotherapeutic agent that has been used to treat urinary tract infections since the 1960s. Today, the incidence of multidrug-resistant (MDR) bacterial strains is on the rise worldwide. This has resulted in repurposing, whereby during the ongoing research on nitroxoline, the possibility of its wide use has been demonstrated, not only in treatment against resistant pathogens, but also potential broad anti-cancer applications.
Aim of the study
The purpose of our work was to review scientific articles and show the multi-potential - anti-pathogenic and anti-tumor use of nitroxoline.
Methods and materials
We reviewed the English-language literature in the PubMed database, using the key words: „Nitroxoline”, „Nitroxoline cancer”, „Nitroxoline antibacterial use”
Results
Analysis of studies has shown that nitroxoline, currently used in benign urinary tract infections, is also applicable in the treatment of urinary tract infections caused by multidrug-resistant bacteria (MRD). It is also active against drug-resistant fungi and mycobacteria. Repurposing has also demonstrated the anticancer effects of nitroxoline through inhibition proliferation, induction apoptosis of tumor cells and other mechanisms, making it likely that nitroxoline will be used in cancer treatment regimens in the future.
Conclusion
Nitroxoline has found widespread use in the treatment of urinary tract infections caused by multidrug-resistant bacteria (MRD) and by strains of resistant fungi, which in today's world are spreading and increasing their drug resistance. Repurposing has shown promising anticancer activity of nitroxoline in the treatment of urinary tract cancers and more. The data supporting the effects of nitroxoline seem promising, suggesting the rationale for future clinical trials to further our understanding of the exact mechanisms of action and use of nitroxoline in oncology treatment.
References
Lin W, Sun J, Sadahira T, Xu N, Wada K, Liu C, Araki M, Xu A, Watanabe M, Nasu Y, Huang P. Discovery and Validation of Nitroxoline as a Novel STAT3 Inhibitor in Drug-resistant Urothelial Bladder Cancer. Int J Biol Sci. 2021 Jul 25;17(12):3255-3267. doi: 10.7150/ijbs.63125. PMID: 34421363; PMCID: PMC8375225.
Ren L, Jiang M, Xue D, Wang H, Lu Z, Ding L, Xie H, Wang R, Luo W, Xu L, Wang M, Yu S, Cheng S, Xia L, Yu H, Huang P, Xu N, Li G. Nitroxoline suppresses metastasis in bladder cancer via EGR1/circNDRG1/miR-520h/smad7/EMT signaling pathway. Int J Biol Sci. 2022 Aug 8;18(13):5207-5220. doi: 10.7150/ijbs.69373. PMID: 35982887; PMCID: PMC9379395.
Xu N, Lin W, Sun J, Sadahira T, Xu A, Watanabe M, Guo K, Araki M, Li G, Liu C, Nasu Y, Huang P. Nitroxoline inhibits bladder cancer progression by reversing EMT process and enhancing anti-tumor immunity. J Cancer. 2020 Sep 23;11(22):6633-6641. doi: 10.7150/jca.47025. PMID: 33046984; PMCID: PMC7545671.
Xu N, Huang L, Li X, Watanabe M, Li C, Xu A, Liu C, Li Q, Araki M, Wada K, Nasu Y, Huang P. The Novel Combination of Nitroxoline and PD-1 Blockade, Exerts a Potent Antitumor Effect in a Mouse Model of Prostate Cancer. Int J Biol Sci. 2019 Mar 9;15(5):919-928. doi: 10.7150/ijbs.32259. PMID: 31182913; PMCID: PMC6535792.
Chang WL, Hsu LC, Leu WJ, Chen CS, Guh JH. Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer: a crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation. Oncotarget. 2015 Nov 24;6(37):39806-20. doi: 10.18632/oncotarget.5655. PMID: 26447757; PMCID: PMC4741862.
Zhang QI, Wang S, Yang D, Pan K, Li L, Yuan S. Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing. Oncol Lett. 2016 May;11(5):3265-3272. doi: 10.3892/ol.2016.4380. Epub 2016 Mar 29. PMID: 27123101; PMCID: PMC4841112.
Lazovic J, Guo L, Nakashima J, Mirsadraei L, Yong W, Kim HJ, Ellingson B, Wu H, Pope WB. Nitroxoline induces apoptosis and slows glioma growth in vivo. Neuro Oncol. 2015 Jan;17(1):53-62. doi: 10.1093/neuonc/nou139. Epub 2014 Jul 28. PMID: 25074541; PMCID: PMC4483047.
Dobrindt U, Wami HT, Schmidt-Wieland T, Bertsch D, Oberdorfer K, Hof H. Compared with Cotrimoxazole Nitroxoline Seems to Be a Better Option for the Treatment and Prophylaxis of Urinary Tract Infections Caused by Multidrug-Resistant Uropathogens: An In Vitro Study. Antibiotics (Basel). 2021 May 28;10(6):645. doi: 10.3390/antibiotics10060645. PMID: 34071539; PMCID: PMC8230139.
Wykowski R, Fuentefria AM, de Andrade SF. Antimicrobial activity of clioquinol and nitroxoline: a scoping review. Arch Microbiol. 2022 Jul 30;204(8):535. doi: 10.1007/s00203-022-03122-2. PMID: 35907036; PMCID: PMC9362210.
Fuchs F, Hof H, Hofmann S, Kurzai O, Meis JF, Hamprecht A. Antifungal activity of nitroxoline against Candida auris isolates. Clin Microbiol Infect. 2021 Nov;27(11):1697.e7-1697.e10. doi: 10.1016/j.cmi.2021.06.035. Epub 2021 Jul 7. PMID: 34245904.
Cherdtrakulkiat R, Boonpangrak S, Sinthupoom N, Prachayasittikul S, Ruchirawat S, Prachayasittikul V. Derivatives (halogen, nitro and amino) of 8-hydroxyquinoline with highly potent antimicrobial and antioxidant activities. Biochem Biophys Rep. 2016 Mar 24;6:135-141. doi: 10.1016/j.bbrep.2016.03.014. PMID: 29214226; PMCID: PMC5689172.
Abouelhassan Y, Yang Q, Yousaf H, Nguyen MT, Rolfe M, Schultz GS, Huigens RW 3rd. Nitroxoline: a broad-spectrum biofilm-eradicating agent against pathogenic bacteria. Int J Antimicrob Agents. 2017 Feb;49(2):247-251. doi: 10.1016/j.ijantimicag.2016.10.017. Epub 2016 Dec 6. PMID: 28110918.
Cherdtrakulkiat R, Lawung R, Nabu S, Tantimavanich S, Sinthupoom N, Prachayasittikul S, Prachayasittikul V. Nitroxoline: a potent antimicrobial agent against multidrug resistant Enterobacteriaceae. EXCLI J. 2019 Jun 26;18:445-453. doi: 10.17179/excli2019-1378. PMID: 31423123; PMCID: PMC6694710.
Kudera T, Doskocil I, Salmonova H, Petrtyl M, Skrivanova E, Kokoska L. In Vitro Selective Growth-Inhibitory Activities of Phytochemicals, Synthetic Phytochemical Analogs, and Antibiotics against Diarrheagenic/Probiotic Bacteria and Cancer/Normal Intestinal Cells. Pharmaceuticals (Basel). 2020 Sep 3;13(9):233. doi: 10.3390/ph13090233. PMID: 32899218; PMCID: PMC7558399.
Principe L, Vecchio G, Sheehan G, Kavanagh K, Morroni G, Viaggi V, di Masi A, Giacobbe DR, Luzzaro F, Luzzati R, Di Bella S. Zinc Chelators as Carbapenem Adjuvants for Metallo-β-Lactamase-Producing Bacteria: In Vitro and In Vivo Evaluation. Microb Drug Resist. 2020 Oct;26(10):1133-1143. doi: 10.1089/mdr.2020.0037. Epub 2020 May 4. PMID: 32364820.
Sobke A, Makarewicz O, Baier M, Bär C, Pfister W, Gatermann SG, Pletz MW, Forstner C. Empirical treatment of lower urinary tract infections in the face of spreading multidrug resistance: in vitro study on the effectiveness of nitroxoline. Int J Antimicrob Agents. 2018 Feb;51(2):213-220. doi: 10.1016/j.ijantimicag.2017.10.010. Epub 2017 Oct 27. PMID: 29111434.
Hof H, Juretschke C. Nitroxoline: an option for the treatment of urinary tract infection with multi-resistant uropathogenic bacteria. Infection. 2019 Jun;47(3):493-495. doi: 10.1007/s15010-018-1253-y. Epub 2018 Nov 17. PMID: 30449013.
Ancuta D, Gorea M, Avram A (2016) Antimicrobial activity of ceramic disks loaded with silver ions and nitroxoline. Bacteriology and Bacterial Zoonoses. https://www.researchgate.net/publication/305618803. Accessed 06 July 2020
Fuchs F, Aldejohann AM, Hoffmann AM, Walther G, Kurzai O, Hamprecht AG. In Vitro Activity of Nitroxoline in Antifungal-Resistant Candida Species Isolated from the Urinary Tract. Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0226521. doi: 10.1128/aac.02265-21. Epub 2022 May 11. PMID: 35543103; PMCID: PMC9211423.
Naber KG, Niggemann H, Stein G, Stein G. Review of the literature and individual patients' data meta-analysis on efficacy and tolerance of nitroxoline in the treatment of uncomplicated urinary tract infections. BMC Infect Dis. 2014 Nov 27;14:628. doi: 10.1186/s12879-014-0628-7. PMID: 25427651; PMCID: PMC4262220.
Hoffmann AM, Wolke M, Rybniker J, Plum G, Fuchs F. In vitro Activity of Repurposed Nitroxoline Against Clinically Isolated Mycobacteria Including Multidrug-Resistant Mycobacterium tuberculosis. Front Pharmacol. 2022 May 26;13:906097. doi: 10.3389/fphar.2022.906097. PMID: 35721137; PMCID: PMC9198898.
WHO (2020). Global Tuberculosis Report 2019Licence. CC BY-NC-SA 3.0 IGO. Geneva: WHO. [Google Scholar] [Ref list]
Mourenza Á, Gil JA, Mateos LM, Letek M. Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing. Antibiotics (Basel). 2020 Aug 28;9(9):550. doi: 10.3390/antibiotics9090550. PMID: 32872158; PMCID: PMC7557778.
Odingo JO, Early JV, Smith J, Johnson J, Bailey MA, Files M, Guzman J, Ollinger J, Korkegian A, Kumar A, Ovechkina Y, Parish T. 8-Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis. Drug Dev Res. 2019 Aug;80(5):566-572. doi: 10.1002/ddr.21531. Epub 2019 Mar 20. PMID: 30893501; PMCID: PMC6767403.
Mirković B, Markelc B, Butinar M, Mitrović A, Sosič I, Gobec S, Vasiljeva O, Turk B, Čemažar M, Serša G, Kos J. Nitroxoline impairs tumor progression in vitro and in vivo by regulating cathepsin B activity. Oncotarget. 2015 Aug 7;6(22):19027-42. doi: 10.18632/oncotarget.3699. PMID: 25848918; PMCID: PMC4662473.
Mitrović A, Kljun J, Sosič I, Uršič M, Meden A, Gobec S, Kos J, Turel I. Organoruthenated Nitroxoline Derivatives Impair Tumor Cell Invasion through Inhibition of Cathepsin B Activity. Inorg Chem. 2019 Sep 16;58(18):12334-12347. doi: 10.1021/acs.inorgchem.9b01882. Epub 2019 Aug 29. PMID: 31464130; PMCID: PMC6751773.
Veschi S, De Lellis L, Florio R, Lanuti P, Massucci A, Tinari N, De Tursi M, di Sebastiano P, Marchisio M, Natoli C, Cama A. Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells. J Exp Clin Cancer Res. 2018 Sep 21;37(1):236. doi: 10.1186/s13046-018-0904-2. PMID: 30241558; PMCID: PMC6151049.
Teague A, Lim KH, Wang-Gillam A. Advanced pancreatic adenocarcinoma: a review of current treatment strategies and developing therapies. Ther Adv Med Oncol. 2015 Mar;7(2):68-84. doi: 10.1177/1758834014564775. PMID: 25755680; PMCID: PMC4346211.
Spadi R, Brusa F, Ponzetti A, Chiappino I, Birocco N, Ciuffreda L, Satolli MA. Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians. World J Clin Oncol. 2016 Feb 10;7(1):27-43. doi: 10.5306/wjco.v7.i1.27. PMID: 26862489; PMCID: PMC4734936.
Xia G, Wang H, Song Z, Meng Q, Huang X, Huang X. Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2). J Exp Clin Cancer Res. 2017 Aug 10;36(1):107. doi: 10.1186/s13046-017-0579-0. PMID: 28797284; PMCID: PMC5553806.
Ammazzalorso A, De Lellis L, Florio R, Bruno I, De Filippis B, Fantacuzzi M, Giampietro L, Maccallini C, Perconti S, Verginelli F, Cama A, Amoroso R. Cytotoxic effect of a family of peroxisome proliferator-activated receptor antagonists in colorectal and pancreatic cancer cell lines. Chem Biol Drug Des. 2017 Nov;90(5):1029-1035. doi: 10.1111/cbdd.13026. Epub 2017 Jul 19. PMID: 28544586.
Kelley RK, Ko AH. Erlotinib in the treatment of advanced pancreatic cancer. Biologics. 2008 Mar;2(1):83-95. doi: 10.2147/btt.s1832. PMID: 19707431; PMCID: PMC2727779.
Cho HR, Kumari N, Thakur N, Vu HT, Kim H, Choi SH. Decreased APE-1 by Nitroxoline Enhances Therapeutic Effect in a Temozolomide-resistant Glioblastoma: Correlation with Diffusion Weighted Imaging. Sci Rep. 2019 Nov 12;9(1):16613. doi: 10.1038/s41598-019-53147-9. PMID: 31719653; PMCID: PMC6851184.
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