Synergistic Interaction of Histone Deacetylase 6- and MEK-Inhibitors in Castration-Resistant Prostate Cancer Cells.
castration-resistance
paclitaxel
prostate cancer
ricolinostat
selumetinib
Journal
Frontiers in cell and developmental biology
ISSN: 2296-634X
Titre abrégé: Front Cell Dev Biol
Pays: Switzerland
ID NLM: 101630250
Informations de publication
Date de publication:
2020
2020
Historique:
received:
18
03
2020
accepted:
19
06
2020
entrez:
6
8
2020
pubmed:
6
8
2020
medline:
6
8
2020
Statut:
epublish
Résumé
In spite of new knowledge on prostate cancer molecular landscape, this has been only partially translated to the therapeutic setting. The activation of Ras/Mitogen-activated protein kinase (MAPK) signaling plays an important role in progression of prostate cancer in which deregulation of histone deacetylases (HDAC) is frequent. Based on the notion that HDAC inhibitors may reactivate the expression of genes favoring cell response to drugs, the aim of this study was to investigate the interaction between the HDAC6-specific inhibitor ricolinostat (ACY1215) and the MEK-inhibitor selumetinib (AZD6244) to identify effective combinations in prostate cancer models. Using cell lines exhibiting differential activation of survival pathways (PC3, DU145, 22Rv1) and following different treatment schedules, a synergistic interaction was observed in all cell models, the drug combination being particularly effective in 22Rv1 cells. Marginal levels of apoptosis were observed in PC3 cells after combined treatment, whereas higher levels were achieved in DU145 and 22Rv1 cells. RNAi-mediated knockdown of HDAC6 in selumetinib-treated 22Rv1 cells resulted in increased apoptosis. Combined treatment suppressed the constitutively deregulated survival pathways in all cell lines. A decrease of androgen receptor (AR)-dependent gene (KLK2, DUSP1) mRNA levels was observed in 22Rv1 treated cells, associated with increased AR cytoplasmatic expression, suggesting AR signaling down-regulation, not involving Hsp90 acetylation. When a taxane was used in combination with AZD6244 and ACY1215 by a simultaneous schedule, a synergistic cytotoxic effect together with increased apoptosis was evidenced in all cell models. These results support a rational use of targeted agents to improve prostate cancer cell apoptotic response.
Identifiants
pubmed: 32754596
doi: 10.3389/fcell.2020.00610
pmc: PMC7365948
doi:
Types de publication
Journal Article
Langues
eng
Pagination
610Informations de copyright
Copyright © 2020 Corno, Arrighetti, Ciusani, Corna, Carenini, Zaffaroni, Gatti and Perego.
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