Prostate cancer (PCa) is a heterogeneous disease and ranked as the second leading cause of cancer-related deaths in males worldwide. The global burden of PCa keeps rising regardless of the emerging cutting-edge technologies for treatment and drug designation. There are a number of treatment options which are effectively treating localised and androgen-dependent PCa (ADPC) through hormonal and surgery treatments. However, over time, these cancerous cells progress to androgen-independent PCa (AIPC) which continuously grow despite hormone depletion. At this particular stage, androgen depletion therapy (ADT) is no longer effective as these cancerous cells are rendered hormone-insensitive and capable of growing in the absence of androgen. AIPC is a lethal type of disease which leads to poor prognosis and is a major contributor to PCa death rates. A natural product-derived compound, curcumin has been identified as a pleiotropic compound which capable of influencing and modulating a diverse range of molecular targets and signalling pathways in order to exhibit its medicinal properties. Due to such multi-targeted behaviour, its benefits are paramount in combating a wide range of diseases including inflammation and cancer disease. Curcumin exhibits anti-cancer properties by suppressing cancer cells growth and survival, inflammation, invasion, cell proliferation as well as possesses the ability to induce apoptosis in malignant cells. In this review, we investigate the mechanism of curcumin by modulating multiple signalling pathways such as androgen receptor (AR) signalling, activating protein-1 (AP-1), phosphatidylinositol 3-kinases/the serine/threonine kinase (PI3K/Akt/mTOR), wingless (Wnt)/ß-catenin signalling, and molecular targets including nuclear factor kappa-B (NF-κB), B-cell lymphoma 2 (Bcl-2) and cyclin D1 which are implicated in the development and progression of both types of PCa, ADPC and AIPC. In addition, the role of microRNAs and clinical trials on the anti-cancer effects of curcumin in PCa patients were also reviewed.

Pleurotus pulmonarius has been reported to have a potent remedial effect on diabetic property and considered to be an alternative for type 2 diabetes mellitus treatment. This study aimed to investigate the antidiabetic properties of ammonium sulphate precipitated protein fractions from P. pulmonarius basidiocarps. Preliminary results demonstrated that 30% (NH4)2SO4 precipitated fraction (F30) inhibited Saccharomyces cerevisiae α-glucosidase activity (24.18%), and 100% (NH4)2SO4 precipitated fraction (F100) inhibited porcine pancreatic α-amylase activity (41.80%). Following RP-HPLC purification, peak 3 from F30 fraction demonstrated inhibition towards α-glucosidase at the same time with meagre inhibition towards α-amylase activity. Characterisation of proteins using MALDI-TOF/TOF MS demonstrated the presence of four different proteins, which could be implicated in the regulation of blood glucose level via various mechanisms. Therefore, this study revealed the presence of four antidiabetic-related proteins which are profilin-like protein, glyceraldehyde-3-phosphate dehydrogenase-like protein, trehalose phosphorylase-like (TP-like) protein, and catalase-like protein. Hence, P. pulmonarius basidiocarps have high potential in lowering blood glucose level, reducing insulin resistance and vascular complications.

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.

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Prostate cancer (PCa) is the most frequent malignancy among men. Most PCa patients initially respond to androgen deprivation therapy (ADT) but eventually gain androgen-independent properties (AIPC), which are currently incurable and develop resistance to treatment. Thus, novel therapeutic agents with fewer side effects to treat AIPC is urgently needed. Diarylpentanoid [1, 5-bis (4-hydroxy-3-methanoxyphenyl)-1, 4-pentadiene-3-one] (MS13), a curcumin analogue, demonstrated dose- and time-dependent growth inhibitory effects on AIPC cells. However, the anti-cancer effects of MS13 on AIPC cells have not been extensively studied. This study aims to investigate the expression of genes associated with Notch, Hedgehog, and chromatin condensation pathways in MS13-treated DU 145 cells. In our previous study, MS13 exhibited greater cytotoxicity effects than curcumin in DU 145 cells with lower EC50 values (approximately 8 µM and 35 µM, respectively). The gene expression analysis of MS13-treated DU 145 cells was further explored using nCounter PanCancer Pathway Panel (Nanostring Technologies, USA). Briefly, DU 145 cells were treated with two times of EC50 value (16 µM) of MS13 for 24 hours. The RNA was extracted from treated and controls cells using the RNeasy Mini Kit (Qiagen, USA). Genes with a filter of two-fold-cut-off, p. adjusted ≤ 0.05, and FDR≤ 0.05 were defined as significant differentially expressed genes (DEGs). The finding demonstrated that several genes were significantly altered in MS13-treated DU 145 cells at 16 µM for 24 hours, in comparison with the controls. A total of 7 significantly DEGs associated with Notch, Hedgehog, and chromatin condensation pathways were selected for further analysis. The DEGs associated with Notch pathway including Jagged Canonical Notch Ligand 1 (JAG1), Delta Like Canonical Notch Ligand 4 (DLL4) and Notch Receptor 1 (NOTCH1) were upregulated, and shown to mediate anti-proliferative, apoptosis as well as inhibit metastasis and angiogenic properties in cancer cells. Meanwhile, the DEGs associated with Hedgehog pathway; Protein Kinase CAMP-Activated Catalytic Subunit Beta (PRKACB), Wnt Family Member 7B (WNT7B), Wnt Family Member 5B (WNT5B) and Chromatin condensation; Histone Deacetylase 6 (HDAC6) were downregulated and implicated in cancer progression, tumorigenesis, metastasis, and cell migration. Moreover, genes such as NOTCH1, PRKACB, WNT7B, and WNT5B were involved in multiple signaling pathways, displaying greater growth inhibition. In conclusion, the findings suggest that MS13 may demonstrate anti-cancer effects through modulating key canonical pathways that enhances tumor-suppressive and inhibits oncogenic genes, indicating a potential therapeutic agent for AIPC. Citation Format: Nurul Azwa Abd. Wahab, Iekhsan Othman, Faridah Abas, Rakesh Naidu. MS13 (1, 5-bis (4-hydroxy-3-methanoxyphenyl)-1, 4-pentadiene-3-one) exhibits anti-cancer properties in androgen-independent prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1035.