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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cognizant Communication Corporation
2021
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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. |
format | Online Article Text |
id | pubmed-8420894 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cognizant Communication Corporation |
record_format | MEDLINE/PubMed |
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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