Dados do Trabalho

Título

SYNTHETIC HYBRID MOLECULES FROM DIHYDROPYRIMIDINONES (DHPM) AND DIHYDROPYRIDINES (DHP) AS AN NEW THERAPEUTIC APPROACH FOR PROSTATE CANCER

Introdução

Prostate cancer (PCa) represents a major cause of cancer mortality among men in developed countries. Patients with recurrent disease initially respond to androgen-deprivation therapy, but the tumor eventually progresses ; in this condition, tumor cells acquire the ability to escape cell death and develop resistance to current therapies. Thus, new therapeutic approaches for PCa management are needed. Advances in medicinal chemistry have boosted the search for new biologically active compounds, including multifunctional compounds designed to interact with multiple targets or different molecular receptors

Objetivo

Herein, we evaluated a new therapeutical approach called “Hybrid-molecules” designed from Dihydropyrimidinones (DHPM), dihydropyridines (DHP) and imidazoles in prostate cancer cell lines

Métodos

Cell viability of 10 hybrid-moecules was assessed in tumorigenic cell lines (PC3 ) and one normal cell lines (PNT2) by MTT and subsequent confocal analysis was performed to asses the internalization of molecules in both cell lines. The predicted targets for de hybrid-molecules VPS074, VPS084 was assessed using CortellisTM Drug Discovery Intelligence (CDDI),SwissADME and ADMETLab platform. The effect on cell signaling and cell death was analyzed by western-blot and flow cytometry. The impact of hybrid-molecules on migration and invasion was also analyzed

Resultados

The hybrid-molecules exhibited highest cytotoxic effect in tumorigenic cells lines. Also, VPS074 demonstrated higher selectivity for PC3 cells. The IC50 of VPS084 (6.4 μM) was significant lower when compared to the Cisplatin (7.5 μM) and VPS074 (21.8 μM) . So, we choose PC3 cells as model to evaluate the functional impact of VPS074 and VPS084. The treatment with hybrid-molecules induced increased levels of PARP (p<0.0001), p21 (p<0.005) and promotes p53 accumulation. Moreover, VPS074 and VPS084 promotes the AKT and Aurora Kinase A inhibition as well as promotes cell cycle arrest in G0/G1phase. Also, VPS084 was able to reduce the invasion and migration compared with DMSO and cisplatin.

Conclusões

Our results suggest that VPS074 and VPS084 promotes cell cycle arrest and inhibition of proliferation, migration and invasion in prostate cancer cells, sugesting that these new therapeutical approach might be a novel promising option prostate cancer treatment.

Palavras-chave

PROSTATE CANCER, , HYBRID-MOLECULES, PRECLINICAL TRIALS

Financiador do resumo

FAPESP, PAIP, CNPq, FAPERGS