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.
Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme / C. Perrotta, F. Buonanno, S. Zecchini, A. Giavazzi, F. Proietti Serafini, E. Catalani, L. Guerra, M.C. Belardinelli, S. Picchietti, A.M. Fausto, S. Giorgi, E. Marcantoni, E. Clementi, C. Ortenzi, D. Cervia. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6(2016), pp. 27281.1-27281.14.
|Titolo:||Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme|
PERROTTA, CRISTIANA (Primo)
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/srep27281|
|Appare nelle tipologie:||01 - Articolo su periodico|