The Histone Deacetylase Inhibitor ITF2357 (Givinostat) Targets Oncogenic BRAF in Melanoma Cells and Promotes a Switch from Pro-Survival Autophagy to Apoptosis

Histone deacetylase inhibitors (HDACI) are epigenetic compounds that have been widely considered very promising antitumor agents. Here, we focus on the effects of the pan-HDAC inhibitor ITF2357 (Givinostat) in comparison with SAHA (Vorinostat) in melanoma cells bearing BRAF V600E oncogenic mutation....

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Published in:Biomedicines 2022-08, Vol.10 (8), p.1994
Main Authors: Celesia, Adriana, Notaro, Antonietta, Franzò, Marzia, Lauricella, Marianna, D’Anneo, Antonella, Carlisi, Daniela, Giuliano, Michela, Emanuele, Sonia
Format: Article
Language:English
Subjects:
Antitumor activity
Antitumor agents
Apoptosis
Autophagy
BRAF
Caspase
Caspase inhibitors
Cell culture
epigenetic modifications
Epigenetics
Experiments
HDAC inhibitors
Histone deacetylase
Kinases
Laboratories
Melanoma
melanoma cells
Mutation
Phosphorylation
Physiological aspects
Proteins
Tumors
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Summary:Histone deacetylase inhibitors (HDACI) are epigenetic compounds that have been widely considered very promising antitumor agents. Here, we focus on the effects of the pan-HDAC inhibitor ITF2357 (Givinostat) in comparison with SAHA (Vorinostat) in melanoma cells bearing BRAF V600E oncogenic mutation. Our results indicate both ITF2357 and SAHA dose-dependently reduce the viability of BRAF-mutated SK-MEL-28 and A375 melanoma cells. The comparison of IC50 values revealed that ITF2357 was much more effective than SAHA. Interestingly, both inhibitors markedly decreased oncogenic BRAF protein expression levels, ITF2357 being the most effective compound. Moreover, the BRAF decrease induced by ITF2357 was accompanied by a decrease in the level of phospho-ERK1/2. The inhibitor of upstream MEK activity, U0126, reduced ERK1/2 phosphorylation and dramatically potentiated the antitumor effect of ITF2357, exacerbating the reduction in the BRAF level. ITF2357 stimulated an early pro-survival autophagic response, which was followed by apoptosis, as indicated by apoptotic markers evaluation and the protective effects exerted by the pan-caspase inhibitor z-VADfmk. Overall, our data indicate for the first time that ITF2357 targets oncogenic BRAF in melanoma cells and induces a switch from autophagy to classic apoptosis, thus representing a possible candidate in melanoma targeted therapy.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines10081994