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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2020 Jul 26

PMID 32708903

Citations 6

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

Affiliations

Soon will be listed here.

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.

Citing Articles

TP5: A Novel Therapeutic Approach Targeting Aberrant and Hyperactive CDK5/p25 for the Treatment of Colorectal Carcinoma.

Amin N, Wang H, Song Q, Bhaskar M, Yadav S, Gilbert M Int J Mol Sci. 2023; 24(14).

PMID: 37511490 PMC: 10380212. DOI: 10.3390/ijms241411733.

Recurrent Glioblastoma: What Is the Route?.

Bosio A, Lombardi G Cancers (Basel). 2023; 15(7).

PMID: 37046689 PMC: 10093407. DOI: 10.3390/cancers15072028.

The role of Cdk5 in neurological disorders.

Ao C, Li C, Chen J, Tan J, Zeng L Front Cell Neurosci. 2022; 16:951202.

PMID: 35966199 PMC: 9368323. DOI: 10.3389/fncel.2022.951202.

Post-translational modifications of CDK5 and their biological roles in cancer.

Gao G, Sun Y, Fang R, Wang Y, Wang Y, He Q Mol Biomed. 2022; 2(1):22.

PMID: 35006426 PMC: 8607427. DOI: 10.1186/s43556-021-00029-0.

DYRK1A Negatively Regulates CDK5-SOX2 Pathway and Self-Renewal of Glioblastoma Stem Cells.

Chen B, McCuaig-Walton D, Tan S, Montgomery A, Day B, Kassiou M Int J Mol Sci. 2021; 22(8).

PMID: 33924599 PMC: 8069695. DOI: 10.3390/ijms22084011.

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