Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme

Cristiana Perrotta, Federico Buonanno, Silvia Zecchini, Alessio Giavazzi, Francesca Proietti Serafini, Elisabetta Catalani, Laura Guerra, Maria Cristina Belardinelli, Simona Picchietti, Anna Maria Fausto, Simone Giorgi, Enrico Marcantoni, Emilio Giuseppe Ignazio Clementi, Claudio Ortenzi, Davide Cervia

Research output: Contribution to journalArticlepeer-review

Abstract

Climacostol, a compound produced by the ciliated protozoan Climacostomum virens, displayed cytotoxic properties in vitro. This study demonstrates that it has anti-tumour potential. Climacostol caused a reduction of viability/proliferation of B16-F10 mouse melanoma cells, a rapidly occurring DNA damage, and induced the intrinsic apoptotic pathway characterised by the dissipation of the mitochondrial membrane potential, the translocation of Bax to the mitochondria, the release of Cytochrome c from the mitochondria, and the activation of Caspase 9-dependent cleavage of Caspase 3. The apoptotic mechanism of climacostol was found to rely on the up-regulation of p53 and its targets Noxa and Puma. In vivo analysis of B16-F10 allografts revealed a persistent inhibition of tumour growth rate when melanomas were treated with intra-tumoural injections of climacostol. In addition, it significantly improved the survival of transplanted mice, decreased tumour weight, induced a remarkable reduction of viable cells inside the tumour, activated apoptosis and up-regulated the p53 signalling network. Importantly, climacostol toxicity was more selective against tumour than non-tumour cells. The anti-tumour properties of climacostol and the molecular events associated with its action indicate that it is a powerful agent that may be considered for the design of pro-apoptotic drugs for melanoma therapy.

Original languageEnglish
Article number27281
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Jun 7 2016

ASJC Scopus subject areas

  • General

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