Effect of nitroxoline on angiogenesis and growth of human bladder cancer.

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Shim JS, Matsui Y, Bhat S, Nacev BA, Xu J, Bhang HE, Dhara S, Han KC, Chong CR, Pomper MG, So A, Liu JO

Effect of nitroxoline on angiogenesis and growth of human bladder cancer.

J Natl Cancer Inst. 2010 Dec 15;102(24):1855-73. doi: 10.1093/jnci/djq457. Epub 2010 Nov 18.

PubMed ID

21088277 [ View in PubMed

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Abstract

BACKGROUND: Angiogenesis plays an important role in tumor growth and metastasis; therefore, inhibition of angiogenesis is a promising strategy for developing new anticancer drugs. Type 2 methionine aminopeptidase (MetAP2) protein is likely a molecular target of angiogenesis inhibitors. METHODS: Nitroxoline, an antibiotic used to treat urinary tract infections, was identified from a high-throughput screen of a library of 175,000 compounds for MetAP2 inhibitors and from a parallel screen using the Johns Hopkins Drug Library to identify currently used clinical drugs that can also inhibit human umbilical vein endothelial cells (HUVEC) proliferation. To investigate the mechanism of action of nitroxoline, inhibition of MetAP2 activity and induction of senescence were assessed in HUVEC. To test the antiangiogenic activity of nitroxoline, endothelial tube formation in Matrigel and microvessel formation in Matrigel plugs in vivo were assessed. Antitumor efficacy of nitroxoline was evaluated in mouse models of human breast cancer xenograft (n = 10) and bladder cancer orthotopic xenograft (n = 11). Furthermore, the mechanism of action of nitroxoline was investigated in vivo. RESULTS: Nitroxoline inhibited MetAP2 activity in vitro (half maximal inhibitory concentration [IC(50)] = 54.8 nM, 95% confidence interval [CI] = 22.6 to 132.8 nM) and HUVEC proliferation (IC(50) = 1.9 muM, 95% CI = 1.54 to 2.39 muM). Nitroxoline inhibited MetAP2 activity in HUVEC in a dose-dependent manner and induced premature senescence in a biphasic manner. Nitroxoline inhibited endothelial tube formation in Matrigel and reduced microvessel density in vivo. Mice (five per group) treated with nitroxoline showed a 60% reduction in tumor volume in breast cancer xenografts (tumor volume on day 30, vehicle vs nitroxoline, mean = 215.4 vs 86.5 mm(3), difference = 128.9 mm(3), 95% CI = 32.9 to 225.0 mm(3), P = .012) and statistically significantly inhibited growth of bladder cancer in an orthotopic mouse model (tumor bioluminescence intensities of vehicle [n = 5] vs nitroxoline [n = 6], P = .045). CONCLUSION: Nitroxoline shows promise as a potential therapeutic antiangiogenic agent.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Nitroxoline	Methionine aminopeptidase 2	Protein	Humans	Yes	Inhibitor	Details