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APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model

Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing th...

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Autores principales: Jin, Guoguo, Yao, Ke, Guo, Zhiping, Zhao, Zhenjiang, Liu, Kangdong, Liu, Fangfang, Chen, Hanyong, Gorja, Dhilli Rao, Reddy, Kanamata, Bode, Ann M., Dong, Ziming, Dong, Zigang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581118/
https://www.ncbi.nlm.nih.gov/pubmed/28881819
http://dx.doi.org/10.18632/oncotarget.18508
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author Jin, Guoguo
Yao, Ke
Guo, Zhiping
Zhao, Zhenjiang
Liu, Kangdong
Liu, Fangfang
Chen, Hanyong
Gorja, Dhilli Rao
Reddy, Kanamata
Bode, Ann M.
Dong, Ziming
Dong, Zigang
author_facet Jin, Guoguo
Yao, Ke
Guo, Zhiping
Zhao, Zhenjiang
Liu, Kangdong
Liu, Fangfang
Chen, Hanyong
Gorja, Dhilli Rao
Reddy, Kanamata
Bode, Ann M.
Dong, Ziming
Dong, Zigang
author_sort Jin, Guoguo
collection PubMed
description Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing therapeutic agents are critical. Aurora kinases play a crucial role in mitosis and selective inhibitors might provide an effective therapeutic treatment for cancer. However, the role of Aurora kinases in EC is still inadequately studied. Here, we identified a novel compound, referred to as APIO-EE-9, which inhibits growth and colony formation and induces apoptosis of esophageal cancer cells. Using computer modeling, we found that APIO-EE-9 interacted with both Aurora A and B in the ATP-binding pocket. APIO-EE-9 inhibited both Aurora A and B kinase activities in a dose-dependent manner. Treatment with APIO-EE-9 substantially reduced the downstream Aurora kinase phosphorylation of histone H3 (Ser10), resulting in formation of multiple nuclei and centrosomes. Additionally, esophageal cancer cells expressing shAurora A or shAurora B kinase exhibited a dramatic reduction in proliferation and colony formation. Injection of these cells as xenografts in mice reduced tumor formation compared to wildtype cells. Importantly, APIO-EE-9 significantly decreased the size of esophageal patient-derived xenograft (PDX) tumors implanted in SCID mice. These results demonstrated that APIO-EE-9 is a specific Aurora kinase inhibitor that could be developed as a therapeutic agent against esophageal cancer.
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spelling pubmed-55811182017-09-06 APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model Jin, Guoguo Yao, Ke Guo, Zhiping Zhao, Zhenjiang Liu, Kangdong Liu, Fangfang Chen, Hanyong Gorja, Dhilli Rao Reddy, Kanamata Bode, Ann M. Dong, Ziming Dong, Zigang Oncotarget Research Paper Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing therapeutic agents are critical. Aurora kinases play a crucial role in mitosis and selective inhibitors might provide an effective therapeutic treatment for cancer. However, the role of Aurora kinases in EC is still inadequately studied. Here, we identified a novel compound, referred to as APIO-EE-9, which inhibits growth and colony formation and induces apoptosis of esophageal cancer cells. Using computer modeling, we found that APIO-EE-9 interacted with both Aurora A and B in the ATP-binding pocket. APIO-EE-9 inhibited both Aurora A and B kinase activities in a dose-dependent manner. Treatment with APIO-EE-9 substantially reduced the downstream Aurora kinase phosphorylation of histone H3 (Ser10), resulting in formation of multiple nuclei and centrosomes. Additionally, esophageal cancer cells expressing shAurora A or shAurora B kinase exhibited a dramatic reduction in proliferation and colony formation. Injection of these cells as xenografts in mice reduced tumor formation compared to wildtype cells. Importantly, APIO-EE-9 significantly decreased the size of esophageal patient-derived xenograft (PDX) tumors implanted in SCID mice. These results demonstrated that APIO-EE-9 is a specific Aurora kinase inhibitor that could be developed as a therapeutic agent against esophageal cancer. Impact Journals LLC 2017-06-16 /pmc/articles/PMC5581118/ /pubmed/28881819 http://dx.doi.org/10.18632/oncotarget.18508 Text en Copyright: © 2017 Jin et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Jin, Guoguo
Yao, Ke
Guo, Zhiping
Zhao, Zhenjiang
Liu, Kangdong
Liu, Fangfang
Chen, Hanyong
Gorja, Dhilli Rao
Reddy, Kanamata
Bode, Ann M.
Dong, Ziming
Dong, Zigang
APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model
title APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model
title_full APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model
title_fullStr APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model
title_full_unstemmed APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model
title_short APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model
title_sort apio-ee-9 is a novel aurora a and b antagonist that suppresses esophageal cancer growth in a pdx mouse model
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581118/
https://www.ncbi.nlm.nih.gov/pubmed/28881819
http://dx.doi.org/10.18632/oncotarget.18508
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