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

Authors :
Emeline Tabouret
Herui Wang
Niranjana Amin
Jinkyu Jung
Romain Appay
Jing Cui
Qi Song
Antonio Cardone
Deric M. Park
Mark R. Gilbert
Harish Pant
Zhengping Zhuang
Source :
Cancers, Vol 12, Iss 7, p 1935 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

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.

Details

Language :
English
ISSN :
12071935 and 20726694
Volume :
12
Issue :
7
Database :
Directory of Open Access Journals
Journal :
Cancers
Publication Type :
Academic Journal
Accession number :
edsdoj.32ff9757f4774b52a2f8def68c447537
Document Type :
article
Full Text :
https://doi.org/10.3390/cancers12071935