Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme.
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.
Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Italy.
Cristiana
C
Perrotta
Laboratory of Protistology and Biology Education, Department of Education, Cultural Heritage and Tourism, Università degli Studi di Macerata, Italy.
Federico
F
Buonanno
Unit of Clinical Pharmacology, University Hospital "Luigi Sacco"-ASST Fatebenefratelli Sacco, Milano, Italy.
Silvia
S
Zecchini
Unit of Clinical Pharmacology, University Hospital "Luigi Sacco"-ASST Fatebenefratelli Sacco, Milano, Italy.
Alessio
A
Giavazzi
Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.
Francesca
F
Proietti Serafini
Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.
Elisabetta
E
Catalani
Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.
Laura
L
Guerra
Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.
Maria Cristina
MC
Belardinelli
Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.
Simona
S
Picchietti
Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.
Anna Maria
AM
Fausto
School of Sciences and Technologies, Section of Chemistry, Università degli Studi di Camerino, Italy.
Simone
S
Giorgi
School of Sciences and Technologies, Section of Chemistry, Università degli Studi di Camerino, Italy.
Enrico
E
Marcantoni
Unit of Clinical Pharmacology, University Hospital "Luigi Sacco"-ASST Fatebenefratelli Sacco; National Research Council-Institute of Neuroscience; Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Italy.|Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.
Emilio
E
Clementi
Laboratory of Protistology and Biology Education, Department of Education, Cultural Heritage and Tourism, Università degli Studi di Macerata, Italy.
Claudio
C
Ortenzi
Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Italy.|Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.
Davide
D
Cervia
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D041681:NIH 3T3 Cells; D012118:Resorcinols / Q000008:administration & dosage* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D012118:Resorcinols; D016159:Tumor Suppressor Protein p53; C453475:climacostol