RESUMO

BACKGROUND: In vitro studies evidenced antitumor effects of omega-3 polyunsaturated fatty acids ([n-3] PUFAs), but their effects on prostate cancer (PCa) remain controversial in epidemiological studies. Here we investigated whether an (n-3) PUFA-enriched diet affects tumor progression in transgenic adenocarcinoma of the mouse prostate (TRAMP), at early (12 weeks age) and advanced stages (20 weeks age). METHODS: TRAMP mice were fed with standard rodent diet (C12, C20) or (n-3) PUFA-enriched diet containing 10% fish oil (T12, T20). A group of 8 weeks age animals fed standard diet was also used for comparison (C8). The ventral prostate was processed for histopathological and immunohistochemical analyses and serum samples submitted to biochemical assays. RESULTS: At early stages, (n-3) PUFA increased the frequency of normal epithelium (3.8-fold) and decreased the frequency of high-grade intraepithelial neoplasia (3.3-fold) and in situ carcinoma (1.9-fold) in the gland, maintaining prostate pathological status similar to C8 group. At advanced stages, 50% of the animals developed a large primary tumor in both C20 and T20, and tumor weight did not differ (C20: 2.2 ± 2.4; T20: 2.8 ± 2.9 g). The ventral prostate of T12 and of T20 animals that did not develop primary tumors showed lower cell proliferation, tissue expressions of androgen (AR) and glucocorticoid (GR) receptors, than their respective controls. For these animals, (n-3) PUFA also avoided an increase in the number of T-lymphocytes, collagen fibers, and αSMA immunoreactivity, and preserved stromal gland microenvironment. (n-3) PUFA also lowered serum triglycerides and cholesterol, regulating the lipid metabolism of TRAMP mice. CONCLUSIONS: (n-3) PUFAs had a protective effect at early stages of PCa, delaying tumor progression in TRAMP mice, in parallel with reductions in cell proliferation, AR, and GR and maintenance of the stromal compartment of the gland. However, (n-3) PUFAs did not prevent the development of primary tumors for the T20 group, reinforcing the need for further investigation at advanced stages of disease.

Assuntos

Adenocarcinoma , Ácidos Graxos Ômega-3 , Neoplasias da Próstata , Humanos , Masculino , Camundongos , Animais , Camundongos Transgênicos , Próstata/patologia , Neoplasias da Próstata/patologia , Adenocarcinoma/patologia , Ácidos Graxos Ômega-3/farmacologia , Processos Neoplásicos , Ácidos Graxos Insaturados/metabolismo , Microambiente Tumoral

RESUMO

Piceatannol (PIC), a polyphenol presents in many vegetables and fruits including yellow passion fruit extract (PFE; Passiflora edulis), has anti-cancer activity, but its molecular targets are still poorly understood. The aims of this study were to investigate the molecular mechanistic actions of PIC in prostate cancer cell lines and to test if the extract from PFE rich in PIC can affect the growth of prostate cancer cells in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The PC-3, 22Rv1, LNCaP, and VCaP prostate cancer cells were exposed to PIC (10-40 µM), and cell viability, lactate measurement, Western blot, and flow cytometric analyses were performed. For an in vivo experiments, eight-week-old TRAMP mice (n = 10 per group each) received an aqueous extract of PFE containing 20 mg of PIC/kg or water (control group) by gavage for 4 or 10 weeks for further analyses. PIC treatment concentration- and time-dependently reduced viability of all cell lines tested. 22Rv1 and LNCaP cells treated with PIC did not exhibit any significant alteration in the intracellular accumulation of lactate. PIC treatment caused G0/G1 phase cell cycle arrest and induction of apoptosis in both LNCaP and 22Rv1 cells. PIC-treated cells exhibited altered protein levels of p53, p21, cyclin D1, and cyclin-dependent kinase 4 (cdk4). The short and long-term PFE treatments also affected p21, cyclin D1 and cdk4 and delayed disease progression in TRAMP, with a decreased incidence of preneoplastic lesions. In conclusion, PIC apparently does not alter glucose metabolism in prostate cancer cells, while cell cycle arrest and p53 modulation are likely important in anti-cancer effects of PIC alone or as a food matrix byproduct in prostate cancer cells, especially those with an androgen-dependent phenotype.