Science and Technology Production

--- - THE COMBINATION OF DAPT AND ENZALUTAMIDE IMPROVES IN VIVO PC3 PROSTATE TUMORS

Congress

Authorship:

Agustina, Chimento ; Sofía, Herrera ; Daiana, Vitale ; Licina, Tessone ; Laura, Alaniz ; CRISTINA, SILVIA CAROLINA

Date:

2023

Publishing House and Editing Place:

---

Summary *

Prostate cancer (PCa) is one of the most frequent cancers among males. New AR inhibitor agents such as Enzalutamide (Enz) have been released; but, their efficacy is insufficient. There is strong evidence that involves Notch pathway in prostate development but its role in PCa generation and progression is poorly understood.We previously demonstrated AR and Notch receptor expression in prostate cancer PC3 cells in vitro and we observed significantly reduced viability of PC3 cells treated both with Enz (p=0.0018;n=3), an inhibitor of Notch signaling DAPT (p=0.0027;n=3) and also with the combined Enz-DAPT treatment (p=0.0043;n=3). In this work, we aimed to study the effect of Notch system inhibition together with Enz treatment in prostate tumor development in vivo. We injected PC3 cells subcutaneously in Nude mice and we treated them three times/week during 3 weeks with DAPT (i.p. 12 mg/kg,n=4), Enz (i.p. 10 mg/kg,n=3) or the combination of Enz-DAPT (n=3). Control animals received vehicle (DMSO) (n=4). No differences were observed in the single treatments, but tumor growth reached a reduction along the second week in the Enz-DAPT animals compared to controls (p<0,05). For proliferation index calculation, Ki67+ immunostaining was performed and nuclei in the hotspot areas were manually quantified and normalized to total nuclei in these areas. We found a trend of reduction of Ki-67 index in the group of Enz-DAPT treated animals compared to controls. We observed a trend of reduction of a target gene of Notch Hes1 and Notch1 receptor by RT-qPCR in the combined treatment as well.Our study shows in vitro and in vivo activation of the Notch pathway in tumors PC3 cells, which would be involved in tumor cell proliferation. Based on our results arised from in vivo experiments, a combined approach with inhibitors of both pathways could be more effective than any isolated one. Further studies are needed to potentiate this combined treatment thinking of patients with aggressive PCa. Information provided by the agent in SIGEVA

Key Words

Prostate cancer Androgen receptor pathways Notch pathway