Inflammation and neoplastic lesions in the prostate: chemopreventive treatments with Goniothalamin and Celecoxib in senile mice and transgenic adenocarcinoma of the mouse prostate (TRAMP)

Author(s)

Larissa Akemi Kido

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2017-04-19

Examining board members

Valéria Helena Alves Cagnon; Rejane Maira Góes; Ana Carolina de Mattos Zeri; Adriana Fogagnolo Maurício; Bruno César Schimming

• Advisor: Valéria Helena Alves Cagnon

Abstract

Inflammation plays an important role in the onset and progression of prostatic lesions, and is often related to the aging process. Therefore, chemopreventive therapy has emerged as a new therapeutic approach, which aims to mitigate and / or block the primary cancer initiation agents, such as inflammation. Thus, the aim of this thesis was to evaluate the chemopreventive potencial of Celecoxib, a nonsteroidal anti-inflammatory drug, and Goniothalamin (GTN), a styril-lactone present in plants of Goniothalamus genus, by means parameters related to morphology, inflammation, proliferation, apoptosis and cell survival in the ventral prostate in senile (FVB) and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. In addition, in order to characterize the risk for cancer development in the senile prostate, we proposed a new evaluation method based on the comparison of the prostate metabolomic profile of senile animals with the TRAMP prostate. Senile FVB mice (52 weeks old) and TRAMP mice (8 weeks old) were treated for 4 weeks with Celecoxib (10 mg / kg / day) or GTN (150mg / kg / day). Both treatments were administered separately in each experimental group. The TRAMP mice treated with Celecoxib or GTN were divided into two groups: 1) immediate response group, i.e., euthanized immediately after the treatment; 2) late response group, i. e. euthanized after 10 weeks of treatment. For nuclear magnetic resonance analysis (1H-NMR), three experimental groups were evaluated: SENILE FVB mice; and TRAMP mice at 8 (T8) and 12 (T12) weeks of age. After that, the prostate ventral lobe was collected for light microscopy, ELISA, immunohistochemistry, and western blotting analyses. The aging process contributed to morphological changes in the prostate such as atrophy and proliferation in the epithelial compartment, stromal hypertrophy and hyperplasia, and an increase of pro-inflammatory mediators (COX-2, NFKB, TNF-?, IL-6 and IL- 1?). Similarly, increased levels of these inflammatory markers, as well as factors related to proliferation (STAT-3 and IGFR-1), were observed in the prostate of TRAMP mice throughout the disease progression. GTN and Celecoxib treatments were effective in controlling the inflammation and led to glandular morphology recovery in both animal models. Our data highlighted GTN efficacy in TRAMP groups, which showed a significant decrease in the incidence of premalignant and malignant lesions. These results were confirmed by a significant decrease in the PCNA cell proliferation marker. Celecoxib was effective in COX-2 pathway regulatation, even at advanced cancer stages. However, GTN treatment influenced greater amount of pathways involved in prostate cancer development, when compared to Celecoxib. In the senile model, both treatments prevented the onset of proliferative lesions and increased cell apoptosis. In relation to the metabolomic analysis, the results showed a significant increase in the glycerophospholipid metabolism during senescence, and a citrate decrease in the cancer model. In conclusion, this study confirmed the senile prostatic microenvironment susceptibility to the development of neoplasias through the protein and metabolic increase of proliferative process markers. Furthermore, the control of the inflammatory process at early stages of the development of precancerous lesions in senile and TRAMP mice was key to downregulate signaling pathways involved in proliferative processes (AU)

• FAPESP's process: 13/01294-8 - The controversial relationship between inflammation and prostatic lesions: treatment with Celecoxib and Goniothalamin in senile and Tramp mice
• Grantee: Larissa Akemi Kido de Barros
• Support Opportunities: Scholarships in Brazil - Doctorate