Diarylpentanoid (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) (MS13) Exhibits Anti-proliferative, Apoptosis Induction and Anti-migration Properties on Androgen-independent Human Prostate Cancer by Targeting Cell Cycle-Apoptosis and PI3K Signalling Pathways.

Nurul Azwa Abd Wahab,Rakesh Naidu,Iekhsan Othman,Faridah Abas

doi:10.3389/fphar.2021.707335

Nurul Azwa Abd Wahab, Rakesh Naidu + Show 2 more

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https://doi.org/10.3389/fphar.2021.707335

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Abstract

Diarylpentanoids exhibit a high degree of anti-cancer activity and stability in vitro over curcumin in prostate cancer cells. Hence, this study aims to investigate the effects of a diarylpentanoid, 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (MS13) on cytotoxicity, anti-proliferative, apoptosis-inducing, anti-migration properties, and the underlying molecular mechanisms on treated androgen-independent prostate cancer cells, DU 145 and PC-3. A cell viability assay has shown greater cytotoxicity effects of MS13-treated DU 145 cells (EC50 7.57 ± 0.2 µM) and PC-3 cells (EC50 7.80 ± 0.7 µM) compared to curcumin (EC50: DU 145; 34.25 ± 2.7 µM and PC-3; 27.77 ± 6.4 µM). In addition, MS13 exhibited significant anti-proliferative activity against AIPC cells compared to curcumin in a dose- and time-dependent manner. Morphological observation, increased caspase-3 activity, and reduced Bcl-2 protein levels in these cells indicated that MS13 induces apoptosis in a time- and dose-dependent. Moreover, MS13 effectively inhibited the migration of DU 145 and PC-3 cells. Our results suggest that cell cycle-apoptosis and PI3K pathways were the topmost significant pathways impacted by MS13 activity. Our findings suggest that MS13 may demonstrate the anti-cancer activity by modulating DEGs associated with the cell cycle-apoptosis and PI3K pathways, thus inhibiting cell proliferation and cell migration as well as inducing apoptosis in AIPC cells.

Highlights

Prostate cancer (PCa) is the most common malignancy and the second-leading cause of cancer-related death among men worldwide (Crawford, 2003)
To evaluate the in vitro dose-dependent cytotoxicity and selectivity index effects, DU 145, PC-3 and WRL 68 cell lines were incubated with different concentration of MS13
In PC-3 treated cells, 57% cell viability was noted at 25 μM, while 10% was observed at 50 μM (Figures 2A,B,D,E)

Summary

Introduction

Prostate cancer (PCa) is the most common malignancy and the second-leading cause of cancer-related death among men worldwide (Crawford, 2003). Androgens and its receptor are the dominant modulators of normal prostate growth and PCa tumorigenesis (Banerjee et al, 2018). Androgen depletion therapy (ADT) is extensively used to treat PCa and effective in controlling hormone-naïve PCa (Huggins and Hodges, 2002). Over time, these patients eventually progress to a more aggressive and lethal form of PCa, known as androgen-independent PCa (AIPC) (Aragon-Ching and Dahut, 2007). Despite the advancement of PCa therapy, the mortality rate remains high, mainly among AIPC patients (Isaacs, 1994; Fiñones et al, 2013). There is an urgent need to identify novel and potent anti-cancer compound to treat AIPC

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