Synergistic effect of abiraterone acetate and PI3K/mTORC1/2 inhibitor (NVP-BEZ235) on prostate carcinogenesis in Fischer 344 rats

• Grant number: 13/22604-5
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): April 01, 2014
• Effective date (End): March 31, 2017
• Field of knowledge: Biological Sciences - Morphology
• Principal Investigator: Wellerson Rodrigo Scarano
• Grantee: Bianca Facchim Gonçalves
• Home Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Prostate cancer is an endocrine related disease driven by androgens, consequently androgen deprivation has been used as the main treatment for significant reduction of these tumors. The antiandrogen abiraterone acetate, a CYP17 inhibitor has been used to treat advanced stages of the disease. However its use can trigger drug resistance mechanisms requiring additional treatments to control disease progression. In this direction the association of this therapy with inhibitors of signaling pathways related to progression of prostate carcinogenesis, such as the PI3K/Akt, appears an alternative strategy for effective treatment of disease. The aim of this project is to evaluate the effect of single and combined abiraterone acetate and PI3K/mTORC1/2 inhibitor (NVP - BEZ235 ) treatment on prostate carcinogenesis. For this, 60 male rats (Fischer 344) at 12 weeks of age, will receive daily subcutaneous doses of 100mg/kg of testosterone cypionate for 3 consecutive days. Subsequently, the animals will be anesthetized for inoculation of N-methyl -N- nitrosourea (15 mg / kg) in the ventral prostate lobe capsule. One week after the administration of the carcinogen the animals will receive subcutaneous doses of 5mg/kg testosterone cypionate twice a week for 120 days. After tumor induction animals will undergo ultrasound exams to check for prostate lesions and then randomly divided into four groups: (I) control animals which will receive subcutaneous injections of mineral oil and/or saline by gavage daily for 30 days; (AA) animals will receive daily intraperitoneal doses of abiraterone acetate (0.5 mmol/kg/day) for 30 days; (BEZ) animals will receive daily NVP - BEZ 235 (45mg/kg/dia) by gavage for 30 days; (AA+BEZ) animals will receive daily doses of abiraterone acetate and NVP BEZ - 235 for 30 days. At the end of the experimental period, samples of the ventral prostate lobe of all animals will be collected and submitted to histopathological analysis, immunohistochemistry, Western blotting and gene expression by RT - qPCR of markers and genes involved in signaling pathways activated during prostate carcinogenesis.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GONCALVES, BIANCA FACCHIM; PEGORIN DE CAMPOS, SILVANA GISELE; FAVARO, WAGNER JOSE; BRANDT, JOYCE ZALOTTI; PINHO, CRISTIANE FIGUEIREDO; JUSTULIN, LUIS ANTONIO; TABOGA, SEBASTIAO ROBERTO; SCARANO, WELLERSON RODRIGO. Combinatorial Effect of Abiraterone Acetate and NVP-BEZ235 on Prostate Tumor Progression in Rats. HORMONES & CANCER, v. 9, n. 3, p. 175-187, JUN 2018. Web of Science Citations: 0.