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

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.

Anti-Cancer Mechanisms of Diarylpentanoid MS17 (1,5-Bis(2-hydroxyphenyl)-1,4-pentadiene-3-one) in Human Colon Cancer Cells: A Proteomics Approach

“…In addition, curcumin has been reported to induce apoptosis in CRC cells via the upregulation of caspase-3 and downregulation of Bcl-2 protein [ 92 , 93 , 94 , 95 ]. Numerous curcumin analogues have been reported to promote apoptosis in cancer cells by inducing caspase-3 cleavage/activity and Bcl-2 protein suppression [ 63 , 96 , 97 , 98 , 99 ]. For instance, our group also reported another curcumin analogue MS13 significantly promoted caspase-3 activity and downregulated Bcl-2 protein expression in SW480 and SW620 cells [ 64 ].…”

“…The different morphological criteria were used to clarify healthy live cells, early or late apoptotic and necrotic cells based on reference protocols as previously described [ 63 , 268 ].…”

“…In comparison, curcumin possesses two aromatic rings linked by a seven-carbon tether that contains two α,β-unsaturated ketone moieties [ 59 ]. Multiple studies have shown that DAPs, such as CDF, EF24, GO-Y030 and UBS109, are superior to curcumin molecules in inducing growth-suppressive and apoptosis activities in a wide range of cancer cells, including breast [ 60 ], pancreatic [ 61 ], lung [ 62 ], prostate [ 63 ] and CRC [ 64 ]. For example, EF24 is a fluorinated DAP that induces apoptosis and cell cycle arrest in CRC cells via accumulation of reactive oxygen species (ROS), mitochondrial dysfunction and activation of caspase-dependent pathways [ 65 ].…”

Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities

“…On the basis of morphological observations, increased caspase-3 activity, and reduced Bcl-2 protein levels in these cells, the authors concluded that curcumin A induces apoptosis and inhibits DU 145 and PC-3 cell migration. They suggested that the curcumin A anticancer activity is due to the modulation of the differentially expressed genes (DEGs) associated with the cell cycle apoptosis and PI3K pathways [43]. Additionally, Tajuddin and co-workers reported that curcumin A (10) exhibits a higher inhibitory effect on two types of non-small-cell lung cancer (NSCLC) cells-squamous cell carcinoma (NCI-H520, EC 50 = 4.7 ± 0.1 µM) and adenocarcinoma (NCI-H23, EC 50 = 3.7 ± 0.4 µM)-compared to curcumin (NCI-H520, EC 50 = 25.2 ± 1.7 µM; and NCI-H23, EC 50 = 18.5 ± 0.7 µM).…”

Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities

“…On the basis of morphological observations, increased caspase-3 activity, and reduced Bcl-2 protein levels in these cells, the authors concluded that curcumin A induces apoptosis and inhibits the DU 145 and PC-3 cell migration. They suggested that the curcumin A anti-cancer activity is due to modulation of differentially expressed genes (DEGs) associated with the cell cycle-apoptosis and PI3K pathways [36]. Additionally, Tajuddin and co-workers reported that curcumin A (10) exhibits higher inhibitory effect on two types of non-small cell lung cancer (NSCLC) cells -squamous cell carcinoma (NCI-H520, EC50 = 4.7±0.1 μM) and adenocarcinoma (NCI-H23, EC50 = 3.7±0.4 μM) -compared to curcumin (NCI-H520, EC50 = 25.2 ± 1.7 μM; and NCI-H23, EC50 = 18.5 ± 0.7 μM).…”