Lestaurtinib inhibits Citron kinase activity and medulloblastoma growth through induction of DNA damage, apoptosis and cytokinesis failure

Gianmarco Pallavicini; Giorgia Iegiani; Roberta Parolisi; Alessia Ferraro; Francesca Garello; Valeria Bitonto; Enzo Terreno; Marta Gai; Ferdinando Di Cunto

doi:10.3389/fonc.2023.1202585

Lestaurtinib inhibits Citron kinase activity and medulloblastoma growth through induction of DNA damage, apoptosis and cytokinesis failure

Front Oncol. 2023 Jun 19:13:1202585. doi: 10.3389/fonc.2023.1202585. eCollection 2023.

Authors

Gianmarco Pallavicini^{1

2}, Giorgia Iegiani^{1

2}, Roberta Parolisi^{1

2}, Alessia Ferraro^{1

2}, Francesca Garello³, Valeria Bitonto³, Enzo Terreno³, Marta Gai³, Ferdinando Di Cunto^{1

2}

Affiliations

¹ Neuroscience Institute Cavalieri Ottolenghi, Turin, Italy.
² Department of Neuroscience 'Rita Levi Montalcini', University of Turin, Turin, Italy.
³ Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.

Abstract

Introduction: Medulloblastoma (MB), the most common malignant pediatric brain tumor, is currently treated with surgery followed by radiation and chemotherapy, which is accompanied by severe side effects, raising the need for innovative therapies. Disruption of the microcephaly-related gene Citron kinase (CITK) impairs the expansion of xenograft models as well as spontaneous MB arising in transgenic mice. No specific CITK inhibitors are available.

Methods: Lestaurtinib, a Staurosporine derivative also known as CEP-701, inhibits CITK with IC50 of 90 nM. We therefore tested the biological effects of this molecule on different MB cell lines, as well as in vivo, injecting the drug in MBs arising in SmoA1 transgenic mice.

Results: Similar to CITK knockdown, treatment of MB cells with 100 nM Lestaurtinib reduces phospho-INCENP levels at the midbody and leads to late cytokinesis failure. Moreover, Lestaurtinib impairs cell proliferation through CITK-sensitive mechanisms. These phenotypes are accompanied by accumulation of DNA double strand breaks, cell cycle block and TP53 superfamily activation in vitro and in vivo. Lestaurtinib treatment reduces tumor growth and increases mice survival.

Discussion: Our data indicate that Lestaurtinib produces in MB cells poly-pharmacological effects extending beyond the inhibition of its validated targets, supporting the possibility of repositioning this drug for MB treatment.

Keywords: CitK; Lestaurtinib; drug repurposing; medulloblastoma; preclinical studies.

Grants and funding

This work was mainly supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) with grant IG23341 to FD. GP was supported by a fellowship from AIRC. The contribution of the University of Torino ex-60% fund to FD is also gratefully acknowledged. GI and AF were supported by a PhD fellowship from the Italian Ministry of University and Research (MIUR).