Effect of nitroxoline on angiogenesis and growth of human bladder cancer

Joong Sup Shim, Yoshiyuki Matsui, Shridhar Bhat, Benjamin A. Nacev, Jing Xu, Hyo Eun C Bhang, Surajit Dhara, Kee Chung Han, Curtis R. Chong, Martin Gilbert Pomper, Alan So, Jun Liu

Research output: Contribution to journalArticle

Abstract

BackgroundAngiogenesis 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 175000 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 [IC50] = 54.8 nM, 95% confidence interval [CI] = 22.6 to 132.8 nM) and HUVEC proliferation (IC50 = 1.9 μM, 95% CI = 1.54 to 2.39 μM). 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 mm3, difference = 128.9 mm3, 95% CI = 32.9 to 225.0 mm3, 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.

Original languageEnglish (US)
Pages (from-to)1855-1873
Number of pages19
JournalJournal of the National Cancer Institute
Volume102
Issue number24
DOIs
StatePublished - Dec 15 2010

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Urinary Bladder Neoplasms
Growth
Human Umbilical Vein Endothelial Cells
Heterografts
Angiogenesis Inhibitors
Confidence Intervals
Microvessels
Tumor Burden
Inhibitory Concentration 50
nitroxoline
Cell Proliferation
Pharmaceutical Preparations
Breast Neoplasms
Urinary Tract Infections
Neoplasms
Neoplasm Metastasis
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Effect of nitroxoline on angiogenesis and growth of human bladder cancer. / Shim, Joong Sup; Matsui, Yoshiyuki; Bhat, Shridhar; Nacev, Benjamin A.; Xu, Jing; Bhang, Hyo Eun C; Dhara, Surajit; Han, Kee Chung; Chong, Curtis R.; Pomper, Martin Gilbert; So, Alan; Liu, Jun.

In: Journal of the National Cancer Institute, Vol. 102, No. 24, 15.12.2010, p. 1855-1873.

Research output: Contribution to journalArticle

Shim, JS, Matsui, Y, Bhat, S, Nacev, BA, Xu, J, Bhang, HEC, Dhara, S, Han, KC, Chong, CR, Pomper, MG, So, A & Liu, J 2010, 'Effect of nitroxoline on angiogenesis and growth of human bladder cancer', Journal of the National Cancer Institute, vol. 102, no. 24, pp. 1855-1873. https://doi.org/10.1093/jnci/djq457
Shim, Joong Sup ; Matsui, Yoshiyuki ; Bhat, Shridhar ; Nacev, Benjamin A. ; Xu, Jing ; Bhang, Hyo Eun C ; Dhara, Surajit ; Han, Kee Chung ; Chong, Curtis R. ; Pomper, Martin Gilbert ; So, Alan ; Liu, Jun. / Effect of nitroxoline on angiogenesis and growth of human bladder cancer. In: Journal of the National Cancer Institute. 2010 ; Vol. 102, No. 24. pp. 1855-1873.
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title = "Effect of nitroxoline on angiogenesis and growth of human bladder cancer",
abstract = "BackgroundAngiogenesis 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 175000 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 [IC50] = 54.8 nM, 95{\%} confidence interval [CI] = 22.6 to 132.8 nM) and HUVEC proliferation (IC50 = 1.9 μM, 95{\%} CI = 1.54 to 2.39 μM). 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 mm3, difference = 128.9 mm3, 95{\%} CI = 32.9 to 225.0 mm3, 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.",
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T1 - Effect of nitroxoline on angiogenesis and growth of human bladder cancer

AU - Shim, Joong Sup

AU - Matsui, Yoshiyuki

AU - Bhat, Shridhar

AU - Nacev, Benjamin A.

AU - Xu, Jing

AU - Bhang, Hyo Eun C

AU - Dhara, Surajit

AU - Han, Kee Chung

AU - Chong, Curtis R.

AU - Pomper, Martin Gilbert

AU - So, Alan

AU - Liu, Jun

PY - 2010/12/15

Y1 - 2010/12/15

N2 - BackgroundAngiogenesis 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 175000 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 [IC50] = 54.8 nM, 95% confidence interval [CI] = 22.6 to 132.8 nM) and HUVEC proliferation (IC50 = 1.9 μM, 95% CI = 1.54 to 2.39 μM). 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 mm3, difference = 128.9 mm3, 95% CI = 32.9 to 225.0 mm3, 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.

AB - BackgroundAngiogenesis 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 175000 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 [IC50] = 54.8 nM, 95% confidence interval [CI] = 22.6 to 132.8 nM) and HUVEC proliferation (IC50 = 1.9 μM, 95% CI = 1.54 to 2.39 μM). 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 mm3, difference = 128.9 mm3, 95% CI = 32.9 to 225.0 mm3, 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.

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