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TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma

We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of γH2A.X and phosphorylated ATM. Its to...

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Autores principales: Tabouret, Emeline, Wang, Herui, Amin, Niranjana, Jung, Jinkyu, Appay, Romain, Cui, Jing, Song, Qi, Cardone, Antonio, Park, Deric M., Gilbert, Mark R., Pant, Harish, Zhuang, Zhengping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409269/
https://www.ncbi.nlm.nih.gov/pubmed/32708903
http://dx.doi.org/10.3390/cancers12071935
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author Tabouret, Emeline
Wang, Herui
Amin, Niranjana
Jung, Jinkyu
Appay, Romain
Cui, Jing
Song, Qi
Cardone, Antonio
Park, Deric M.
Gilbert, Mark R.
Pant, Harish
Zhuang, Zhengping
author_facet Tabouret, Emeline
Wang, Herui
Amin, Niranjana
Jung, Jinkyu
Appay, Romain
Cui, Jing
Song, Qi
Cardone, Antonio
Park, Deric M.
Gilbert, Mark R.
Pant, Harish
Zhuang, Zhengping
author_sort Tabouret, Emeline
collection PubMed
description We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of γH2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma.
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spelling pubmed-74092692020-08-25 TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma Tabouret, Emeline Wang, Herui Amin, Niranjana Jung, Jinkyu Appay, Romain Cui, Jing Song, Qi Cardone, Antonio Park, Deric M. Gilbert, Mark R. Pant, Harish Zhuang, Zhengping Cancers (Basel) Article We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of γH2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma. MDPI 2020-07-17 /pmc/articles/PMC7409269/ /pubmed/32708903 http://dx.doi.org/10.3390/cancers12071935 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tabouret, Emeline
Wang, Herui
Amin, Niranjana
Jung, Jinkyu
Appay, Romain
Cui, Jing
Song, Qi
Cardone, Antonio
Park, Deric M.
Gilbert, Mark R.
Pant, Harish
Zhuang, Zhengping
TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma
title TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma
title_full TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma
title_fullStr TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma
title_full_unstemmed TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma
title_short TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma
title_sort tp5, a peptide inhibitor of aberrant and hyperactive cdk5/p25: a novel therapeutic approach against glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409269/
https://www.ncbi.nlm.nih.gov/pubmed/32708903
http://dx.doi.org/10.3390/cancers12071935
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