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Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma

Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetabil...

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Autores principales: Ma, Huan, Nie, Cong, Chen, Ying, Li, Jinmiao, Xie, Yanjie, Tang, Zhixin, Gao, Yang, Ai, Siming, Mao, Yuxiang, Sun, Qian, Lu, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cognizant Communication Corporation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420894/
https://www.ncbi.nlm.nih.gov/pubmed/33573708
http://dx.doi.org/10.3727/096504021X16130322409507
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author Ma, Huan
Nie, Cong
Chen, Ying
Li, Jinmiao
Xie, Yanjie
Tang, Zhixin
Gao, Yang
Ai, Siming
Mao, Yuxiang
Sun, Qian
Lu, Rong
author_facet Ma, Huan
Nie, Cong
Chen, Ying
Li, Jinmiao
Xie, Yanjie
Tang, Zhixin
Gao, Yang
Ai, Siming
Mao, Yuxiang
Sun, Qian
Lu, Rong
author_sort Ma, Huan
collection PubMed
description Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors.
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spelling pubmed-84208942021-09-11 Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma Ma, Huan Nie, Cong Chen, Ying Li, Jinmiao Xie, Yanjie Tang, Zhixin Gao, Yang Ai, Siming Mao, Yuxiang Sun, Qian Lu, Rong Oncol Res Article Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors. Cognizant Communication Corporation 2021-09-07 /pmc/articles/PMC8420894/ /pubmed/33573708 http://dx.doi.org/10.3727/096504021X16130322409507 Text en Copyright © 2021 Cognizant, LLC. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.
spellingShingle Article
Ma, Huan
Nie, Cong
Chen, Ying
Li, Jinmiao
Xie, Yanjie
Tang, Zhixin
Gao, Yang
Ai, Siming
Mao, Yuxiang
Sun, Qian
Lu, Rong
Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma
title Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma
title_full Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma
title_fullStr Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma
title_full_unstemmed Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma
title_short Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma
title_sort therapeutic targeting plk1 by on-01910.na is effective in local treatment of retinoblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420894/
https://www.ncbi.nlm.nih.gov/pubmed/33573708
http://dx.doi.org/10.3727/096504021X16130322409507
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