Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing

Zhang,Qi; Wang,Shanshan; Yang,Dexuan; Pan,Kevin; Li,Linna; Yuan,Shoujun

doi:10.3892/ol.2016.4380

Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing

Authors:
- Qi Zhang
- Shanshan Wang
- Dexuan Yang
- Kevin Pan
- Linna Li
- Shoujun Yuan
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Affiliations: School of Graduate Studies, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China, Jiangsu Asieris Pharmaceuticals Co., Ltd., Taizhou, Jiangsu 225300, P.R. China
Published online on: March 29, 2016 https://doi.org/10.3892/ol.2016.4380
Pages: 3265-3272
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The established urinary antibiotic nitroxoline has recently regained considerable attention, due to its potent activities in inhibiting angiogenesis, inducing apoptosis and blocking cancer cell invasion. These features make nitroxoline an excellent candidate for anticancer drug repurposing. To rapidly advance nitroxoline repurposing into clinical trials, the present study performed systemic preclinical pharmacodynamic evaluation of its anticancer activity, including a methyl thiazolyl tetrazolium assay in vitro and an orthotopic urological tumor assay in vivo. The current study determined that nitroxoline exhibits dose‑dependent anti‑cancer activity in vitro and in urological tumor orthotopic mouse models. In addition, it was demonstrated that the routine nitroxoline administration regimen used for urinary tract infections was effective and sufficient for urological cancer treatment, and 2 to 4‑fold higher doses resulted in obvious enhancement of anticancer efficacy without corresponding increases in toxicity. Furthermore, nitroxoline sulfate, one of the most common metabolites of nitroxoline in the urine, effectively inhibited cancer cell proliferation. This finding increases the feasibility of nitroxoline repurposing for urological cancer treatment. Due to the excellent anticancer activity demonstrated in the present study, and its well‑known safety profile and pharmacokinetic properties, nitroxoline has been approved to enter into a phase II clinical trial in China for non‑muscle invasive bladder cancer treatment (registration no. CTR20131716).

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1	Shim JS and Liu JO: Recent advances in drug repositioning for the discovery of new anticancer drugs. Int J Biol Sci. 10:654–663. 2014. View Article : Google Scholar : PubMed/NCBI
2	Mrhar A, Kopitar Z, Kozjek F, Presl V and Karba R: Clinical pharmacokinetics of nitroxoline. Int J Clin Pharmacol Biopharm. 17:476–481. 1979.PubMed/NCBI
3	Shim JS, Matsui Y, Bhat S, Nacev BA, Xu J, Bhang HE, Dhara S, Han KC, Chong CR, Pomper MG, et al: Effect of nitroxoline on angiogenesis and growth of human bladder cancer. J Natl Cancer Inst. 102:1855–1873. 2010. View Article : Google Scholar : PubMed/NCBI
4	Lazovic J, Guo L, Nakashima J, Mirsadraei L, Yong W, Kim HJ, Ellingson B, Wu H and Pope WB: Nitroxoline induces apoptosis and slows glioma growth in vivo. Neuro Oncol. 17:53–62. 2015. View Article : Google Scholar : PubMed/NCBI
5	Jiang H, Taggart JE, Zhang X, Benbrook DM, Lind SE and Ding WQ: Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline). Cancer Lett. 312:11–17. 2011. View Article : Google Scholar : PubMed/NCBI
6	Mirković B, Renko M, Turk S, Sosič I, Jevnikar Z, Obermajer N, Turk D, Gobec S and Kos J: Novel mechanism of cathepsin B inhibition by antibiotic nitroxoline and related compounds. Chem Med Chem. 6:1351–1356. 2011. View Article : Google Scholar : PubMed/NCBI
7	Gupta SC, Sung B, Prasad S, Webb LJ and Aggarwal BB: Cancer drug discovery by repurposing: Teaching new tricks to old dogs. Trends Pharmacol Sci. 34:508–517. 2013. View Article : Google Scholar : PubMed/NCBI
8	National Research Council: Guide for the Care and Use of Laboratory Animals (8th). The National Academies Press. Washington DC: 2011.
9	Hadaschik BA, Black PC, Sea JC, Metwalli AR, Fazli L, Dinney CP, Gleave ME and So AI: A validated mouse model for orthotopic bladder cancer using transurethral tumour inoculation and bioluminescence imaging. BJU Int. 100:1377–1384. 2007. View Article : Google Scholar : PubMed/NCBI
10	Kang MR, Yang G, Charisse K, Epstein-Barash H, Manoharan M and Li LC: An orthotopic bladder tumor model and the evaluation of intravesical saRNA treatment. J Vis Exp pii. 4207:2012
11	Zhao H, Nolley R, Chen Z and Peehl DM: Tissue slice grafts: An in vivo model of human prostate androgen signaling. Am J Pathol. 177:229–239. 2010. View Article : Google Scholar : PubMed/NCBI
12	Thong AE, Zhao H, Ingels A, Valta MP, Nolley R, Santos J, Young SR and Peehl DM: Tissue slice grafts of human renal cell carcinoma: An authentic preclinical model with high engraftment rate and metastatic potential. Urol Oncol. 32:43.e23–e30. 2014. View Article : Google Scholar
13	Murugasu-Oei B and Dick T: In vitro activity of the chelating agents nitroxoline and oxine against Mycobacterium bovis BCG. Int J Antimicrob Agents. 18:579–582. 2001. View Article : Google Scholar : PubMed/NCBI
14	Reagan-Shaw S, Nihal M and Ahmad N: Dose translation from animal to human studies revisited. FASEB J. 22:659–661. 2008. View Article : Google Scholar : PubMed/NCBI
15	Montironi R and Lopez-Beltran A: The 2004 WHO classification of bladder tumors: A summary and commentary. Int J Surg Pathol. 13:143–153. 2005. View Article : Google Scholar : PubMed/NCBI
16	Santos L, Amaro T, Costa C, Pereira S, Bento MJ, Lopes P, Oliveira J, Criado B and Lopes C: Ki-67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification. Int J Cancer. 105:267–272. 2003. View Article : Google Scholar : PubMed/NCBI
17	Shariat SF, Ashfaq R, Karakiewicz PI, Saeedi O, Sagalowsky AI and Lotan Y: Survivin expression is associated with bladder cancer presence, stage, progression, and mortality. Cancer. 109:1106–1113. 2007. View Article : Google Scholar : PubMed/NCBI
18	Lopez-Beltran A, Scarpelli M, Montironi R and Kirkali Z: 2004 WHO classification of the renal tumors of the adults. Eur Urol. 49:798–805. 2006. View Article : Google Scholar : PubMed/NCBI
19	Albelda SM, Muller WA, Buck CA and Newman PJ: Molecular and cellular properties of PECAM-1 (endoCAM/CD31): A novel vascular cell-cell adhesion molecule. J Cell Biol. 114:1059–1068. 1991. View Article : Google Scholar : PubMed/NCBI
20	Wagenlehner FM, Münch F, Pilatz A, Bärmann B, Weidner W, Wagenlehner CM, Straubinger M, Blenk H, Pfister W, Kresken M and Naber KG: Urinary concentrations and antibacterial activities of nitroxoline at 250 milligrams versus trimethoprim at 200 milligrams against uropathogens in healthy volunteers. Antimicrob Agents Chemother. 58:713–721. 2014. View Article : Google Scholar : PubMed/NCBI
21	Boguski MS, Mandl KD and Sukhatme VP: Drug discovery. Repurposing with a difference. Science. 324:1394–1395. 2009. View Article : Google Scholar : PubMed/NCBI