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Open AccessArticle

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

1
Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2
Team 8 GlioME, CNRS, INP, Inst Neurophysiopathol, Aix-Marseille University, 13005 Marseille, France
3
Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824, USA
4
University of Maryland Institute for Advanced Computer Studies, College Park, MD 20742, USA
5
Department of Neurology and the Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL 60637, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cancers 2020, 12(7), 1935; https://doi.org/10.3390/cancers12071935
Received: 21 May 2020 / Accepted: 13 July 2020 / Published: 17 July 2020
(This article belongs to the Special Issue Recurrent 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 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. View Full-Text
Keywords: glioblastoma; CDK5; radiotherapy; chemotherapy; ATM; DNA damage; targeted therapy glioblastoma; CDK5; radiotherapy; chemotherapy; ATM; DNA damage; targeted therapy
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MDPI and ACS Style

Tabouret, E.; Wang, H.; Amin, N.; Jung, J.; Appay, R.; Cui, J.; Song, Q.; Cardone, A.; Park, D.M.; Gilbert, M.R.; Pant, H.; Zhuang, Z. TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma. Cancers 2020, 12, 1935. https://doi.org/10.3390/cancers12071935

AMA Style

Tabouret E, Wang H, Amin N, Jung J, Appay R, Cui J, Song Q, Cardone A, Park DM, Gilbert MR, Pant H, Zhuang Z. TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma. Cancers. 2020; 12(7):1935. https://doi.org/10.3390/cancers12071935

Chicago/Turabian Style

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. 2020. "TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma" Cancers 12, no. 7: 1935. https://doi.org/10.3390/cancers12071935

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