Effects of orlistat combined with enzalutamide and castration through inhibition of fatty acid synthase in a PC3 tumor-bearing mouse model.

Yeu-Sheng Tyan,Jeng-Jong Hwang,Hui-Yen Chuang,Yen-Po Lee,Wei-Hsun Wang

doi:10.1042/bsr20204203

Abstract

Androgen deprivation therapy (ADT) is one of the typical treatments used for patients with prostate cancer (PCa). ADT, however, may fail when PCa develops castration-resistance. Fatty acid synthase (FASN), a critical enzyme involved in fatty acid synthesis, is found to be up-regulated in PCa. Since enzalutamide and ADT are frequently used for the treatment of PCa, the present study aimed to unravel the underlying mechanism of combination of orlistat, an FASN inhibitor, and enzalutamide using PC3 cell line; and orlistat and castration in PC3 tumor-bearing animal model. Cytotoxicity was determined by AlamarBlue assay. Drug effects on the cell cycle and protein expressions were assayed by the flow cytometry and Western blot. Electromobility shift assay was used to evaluate the NF-κB activity. The tumor growth delay, expressions of the signaling-related proteins, and histopathology post treatments of orlistat and castration were evaluated in PC3 tumor-bearing mouse model. The results showed that orlistat arrested the PC3 cells at the G1 phase of the cell cycle and enhanced the cytotoxic effects of enzalutamide synergistically. Pretreatment with orlistat combined with castration inhibited the tumor growth significantly compared with those of castration and orlistat treatments alone in PC3 tumor-bearing mice. Combination treatment reduced both FASN and NF-κB activities and their downstream effector proteins. The present study demonstrated the synergistic effects of orlistat combined with enzalutamide in vitro and castration in vivo on human PCa.

Highlights

Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer-associated mortality in men [1]
Fatty acid synthase (FASN) has been identified as an oncogene, is up-regulated in tumorigenesis, involved in the palmitoylation of Wnt1, cytoplasmic stabilization of β-catenin and activation of HER1/HER2 tyrosine kinase receptors [22,30,39,40]
FASN functionally plays a key role in de novo synthesis of long-chain fatty acids, which can be stored for Figure 7. 18F-FDG/microPET imaging was used for monitoring therapeutic response in vivo (A) On the 56th day post treatment, microPET was performed at 30 min after intravenous injection of 19.6–20.1 MBq 18F-FDG, and images were acquired for 30 min

Summary

Introduction

Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer-associated mortality in men [1]. Persisting ADT often provides selective pressure on cancer cells and converts them to become more aggressive and treatment-resistant, leading to the development of androgen-independent PCa (AIPC) or castration-resistant PCa (CRPC) [6,7]. These alterations would increase the mortality rates due to the lack of effective alternative targeted therapy [8]. Signals from activated receptor tyrosine kinases (RTKs), Ras-Raf-MEK-ERK1/2 and PI3K/AKT machineries in turn can activate several transcription factors, such as NF-kB and its downstream effector proteins including

Methods

Results

Conclusion