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BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells

BI2536 has been developed as a potential therapeutic agent for various cancers but not in oral cancer cells. Since BI2536 exhibits mitosis-regulating activity which are the most radiosensitive, we hypothesized that BI2536 might modulate the radiosensitivity of oral cancer cells. Human normal fibrobl...

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Autores principales: Cheng, Chieh-Yuan, Liu, Chung-Ji, Huang, Yu-Chuen, Wu, Shu-Hua, Fang, Hsu-Wei, Chen, Yu-Jen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940398/
https://www.ncbi.nlm.nih.gov/pubmed/29765534
http://dx.doi.org/10.18632/oncotarget.25035
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author Cheng, Chieh-Yuan
Liu, Chung-Ji
Huang, Yu-Chuen
Wu, Shu-Hua
Fang, Hsu-Wei
Chen, Yu-Jen
author_facet Cheng, Chieh-Yuan
Liu, Chung-Ji
Huang, Yu-Chuen
Wu, Shu-Hua
Fang, Hsu-Wei
Chen, Yu-Jen
author_sort Cheng, Chieh-Yuan
collection PubMed
description BI2536 has been developed as a potential therapeutic agent for various cancers but not in oral cancer cells. Since BI2536 exhibits mitosis-regulating activity which are the most radiosensitive, we hypothesized that BI2536 might modulate the radiosensitivity of oral cancer cells. Human normal fibroblasts, oral cancer SAS, and OECM1 cells were treated with BI2536 (0–50 nM) and/or radiation (0–4 Gy). MTT assay, Liu's staining, flow cytometry, clonogenic assay, Annexin V/propidium iodide (PI) staining, western blot analysis, and small interfering RNA knockdown experiments were used to assess cell viability, morphology, cell cycle progression, radiation survival, and expression of regulatory proteins in vitro. Male BALB/c nude mice implanted with SAS cells were used to examine the effects of BI2536 in vivo. Treatment with BI2536 preferentially inhibited the viability of SAS and OECM1 cells, but not the normal fibroblasts. Morphological examination and Annexin V/PI staining of BI2536-treated oral cancer cells showed mitotic catastrophe and apoptosis. A DNA histogram revealed BI2536 induced G2/M and upregulation of phosphorylated H3 indicating accumulation in the M phase. BI2536 modulated the expression of PLK1, cell division control protein (Cdc)2, Cdc20, Cdc25c, adenomatous polyposis coli 3, and cyclin B1. At 10 nM, BI2536 exhibited low cytotoxicity, effectively induced mitotic catastrophe, and more importantly, sensitized oral cancer cells to radiotherapy. The animal study showed that BI2536 (10 mg/kg) + radiation (2 Gy) resulted in stronger tumor inhibition than that associated with radiation alone. Our findings showed that BI2536 could be an effective radiosensitizer both in vitro and in vivo.
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spelling pubmed-59403982018-05-15 BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells Cheng, Chieh-Yuan Liu, Chung-Ji Huang, Yu-Chuen Wu, Shu-Hua Fang, Hsu-Wei Chen, Yu-Jen Oncotarget Research Paper BI2536 has been developed as a potential therapeutic agent for various cancers but not in oral cancer cells. Since BI2536 exhibits mitosis-regulating activity which are the most radiosensitive, we hypothesized that BI2536 might modulate the radiosensitivity of oral cancer cells. Human normal fibroblasts, oral cancer SAS, and OECM1 cells were treated with BI2536 (0–50 nM) and/or radiation (0–4 Gy). MTT assay, Liu's staining, flow cytometry, clonogenic assay, Annexin V/propidium iodide (PI) staining, western blot analysis, and small interfering RNA knockdown experiments were used to assess cell viability, morphology, cell cycle progression, radiation survival, and expression of regulatory proteins in vitro. Male BALB/c nude mice implanted with SAS cells were used to examine the effects of BI2536 in vivo. Treatment with BI2536 preferentially inhibited the viability of SAS and OECM1 cells, but not the normal fibroblasts. Morphological examination and Annexin V/PI staining of BI2536-treated oral cancer cells showed mitotic catastrophe and apoptosis. A DNA histogram revealed BI2536 induced G2/M and upregulation of phosphorylated H3 indicating accumulation in the M phase. BI2536 modulated the expression of PLK1, cell division control protein (Cdc)2, Cdc20, Cdc25c, adenomatous polyposis coli 3, and cyclin B1. At 10 nM, BI2536 exhibited low cytotoxicity, effectively induced mitotic catastrophe, and more importantly, sensitized oral cancer cells to radiotherapy. The animal study showed that BI2536 (10 mg/kg) + radiation (2 Gy) resulted in stronger tumor inhibition than that associated with radiation alone. Our findings showed that BI2536 could be an effective radiosensitizer both in vitro and in vivo. Impact Journals LLC 2018-04-20 /pmc/articles/PMC5940398/ /pubmed/29765534 http://dx.doi.org/10.18632/oncotarget.25035 Text en Copyright: © 2018 Cheng et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Cheng, Chieh-Yuan
Liu, Chung-Ji
Huang, Yu-Chuen
Wu, Shu-Hua
Fang, Hsu-Wei
Chen, Yu-Jen
BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells
title BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells
title_full BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells
title_fullStr BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells
title_full_unstemmed BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells
title_short BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells
title_sort bi2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940398/
https://www.ncbi.nlm.nih.gov/pubmed/29765534
http://dx.doi.org/10.18632/oncotarget.25035
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