Combinatorial Effect of Abiraterone Acetate and NVP-BEZ235 on Prostate Tumor Progression in Rats

Abstract

Use of drug combinations that target different pathways involved in the development and progression of prostate cancer (PCa) has emerged as an alternative to overcome the resistance caused by drug monotherapies. The antiandrogen abiraterone acetate and the PI3K/Akt inhibitor NVP-BEZ235 (BEZ235) may be suitable options for the prevention of drug resistance and the inhibition of PCa progression. The aim of the present study was to evaluate whether abiraterone acetate and BEZ235 achieve superior therapeutic effects to either drug administered as monotherapy, in the early stages of PCa in an androgen-dependent system. Our study showed that each drug might impair tumor growth by reducing proliferation and increasing cell death when administered as monotherapy. However, tumor growth continued to progress with each drug monotherapy and some important side effects were related to BEZ. Conversely, when used in combination, the drugs impaired the inflammatory response, decreased hyperplastic lesions, and blocked tumor progression from premalignant to a malignant stage. Our data showed that the strategy to block the androgenic and PI3K/AKT/mTOR pathway is an effective therapeutic option and should be investigated including distinct PI3K pathway inhibitors.

RETRACTED ARTICLE: The PI3K/mTOR dual inhibitor BEZ235 nanoparticles improve radiosensitization of hepatoma cells through apoptosis and regulation DNA repair pathway

“…Radiotherapy is an important traditional tumor treatment, but HCC is highly resistant to local radiotherapy, and intrahepatic tumor radiotherapy may damage normal liver tissue. Mild damage may result only in an increase in Child-Pugh score and serum transaminases, but severe radiation-induced liver disease can occur [25]. In the application of BEZ235 as a sensitizer for radiation therapy of tumors, BEZ235 can make normal liver tissue sensitive to radiation [26].…”

Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

“…This is exemplified by BEZ235, a phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor that blocks AKT phosphorylation (Thr308/Ser473) and can prevent breast [6, 7], glioma [8], and non-small-cell lung cancer growth [9, 10]. Combining BEZ235 with abiraterone acetate, which blocks cytochrome P450 17 alpha-hydroxylase to significantly reduce androgen production, improves therapeutic outcomes in PC [11]. However, PC therapy remains ineffective overall, and more effective alternative treatments are urgently required [12].…”

Herb–drug interactions between androgenic Chinese herbal medicines and androgen receptor antagonist on tumor growth: Studies on two xenograft prostate cancer animal models

“…It is crucial to inhibit androgen signaling either by depriving the tumor from androgens or by blocking the receptor activity. Therefore, androgen deprivation therapy (ADT) is currently the first-line treatment for advanced PCa in clinical practice (Gonçalves et al, 2018). Abiraterone acetate (ABI), a new generation of AR antagonist, could effectively block androgen biosynthesis and suppress AR expression in normal prostate glands and PCa.…”