Abstract
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.
Highlights
Prostate cancer is the second most frequently diagnosed cancer and the third most common cause of cancer-related death in men in Western countries (Siegel et al, 2018)
Sensitivity of the prostate carcinoma DU145, PC3 and 22Rv1 cells to the MEK inhibitor AZD6244, the Histone deacetylases (HDAC) inhibitor ACY1215 and paclitaxel was assessed by growth-inhibition assays following 72 h drug exposure (Supplementary Table 1)
Since a favorable effect and apoptosis induction were obtained when combining ACY1215 and AZD6244 in 22Rv1 cells, that are characterized by marked phospho-ERK1/2 levels, by the expression of full length androgen receptor (AR) and of constitutively active AR variants (Tassinari et al, 2018), we focused our attention on the modulation of AR target genes by qRTPCR analysis and investigated the levels of Kallicrein 2 (KLK2) and dual specifity phosphatase 1 (DUSP1) (Gregory et al, 1998; Vaarala et al, 2012, 466–472)
Summary
Prostate cancer is the second most frequently diagnosed cancer and the third most common cause of cancer-related death in men in Western countries (Siegel et al, 2018). Treatments for metastatic castration-resistant prostate cancer include secondary hormone therapy (Parker and Sartor, 2011; Scher et al, 2011; Ryan et al, 2013; Beer and Tombal, 2014), immunotherapy (Kantoff et al, 2010), radiopharmaceuticals (Parker et al, 2013), and chemotherapy. The activation of the Ras/Mitogen-Activated Protein Kinase (MAPK) signaling pathway plays an important role in progression of prostate cancer to advanced, castration-resistant disease (Bakin et al, 2003). The activation of MAPK, an effector of Ras activation, has been associated with prostate cancer progression (Gioeli et al, 1999). Inhibition of Ras effectors such as MEK could be an effective therapy for advanced prostate cancer (Cossa et al, 2013). A well established set of alterations that could activate MAPK signaling has been identified in prostate cancer and include PTEN loss and, less frequently, BRAF and RAF1 rearrangements (Yap et al, 2016)
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