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Published on: March 9, 2018
Anti-prostate cancer metabolites from the soil-derived Aspergillus neoniveus
Menna Fayek1, Hassan Y Ebrahim1, Heba E Elsayed1
1Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Helwan, Egypt.
Abstract:
Prostate cancer (PCa) ranks as one of the most commonly diagnosed malignancies worldwide. Toxicity, lack of clinical efficacy, and development of resistance phenotypes are the main challenges in the control of prostate malignancies. Notably, castration-resistance prostate cancer (CRPCa) is a highly aggressive and metastatic phenotype of the disease with a poor prognosis and very limited therapeutic options. Herein, we report the isolation and genotypic identification of a soil-derived fungus Aspergillus neoniveus using the PCR-based internal transcribed spacer (ITS) region amplification approach. HPLC/MS investigation of the metabolic profile of the ethyl acetate extract from the fungal biomass revealed tentative identification of forty-five compounds belonging to various chemical classes including γ-butyrolactones, alkaloids, phenolics, and quinoids. Furthermore, the chromatographic purification of microbial extract enabled the identification of nervonic acid methyl ester (1) for the first time from endophytic fungi, as well as acetyl aszonalenin (2), and butyrolactone II (3) for the first time from A. neoniveus. The chemical frameworks of the isolated compounds were identified via extensive spectral analysis including 1 and 2D NMR and MS. The X-ray crystal structure and absolute configuration of acetyl aszonalenin (2) were also determined. Additionally, screening of in vitro anticancer activity of the fungal extract revealed its potential antiproliferative and anti-migratory activities against five different prostate cancer cells (PC3, PC-3M, DU-145, CWR-R1ca, and 22Rv1), including different cells with the castration-resistance phenotype. Moreover, the isolated metabolites significantly inhibited the proliferation, migration, and colonization of human prostate cancer cells at low micromolar levels, thus providing credence for future investigation of these metabolites in relevant anti-prostate cancer animal models. Furthermore, computational target prediction tools identified the cannabinoid G-protein coupled receptors type 1 (CB1) as a potential biological target mediating, at least in part, the anticancer effects of acetylaszonalenin (2). Moreover, molecular modeling and docking studies revealed a favorable binding pose at the CB1 receptor orthosteric ligand pocket aided by multiple polar and hydrophobic interactions with critical amino acids. In conclusion, the Aspergillus neoniveus-derived prenylated indole alkaloid acetylaszonalenin has promising anticancer activity and is amenable to further hit-to-lead optimization for the control of prostate malignancies via modulating CB1 receptors.
Insights
Researchers isolated the fungus Aspergillus neoniveus and identified acetyl aszonalenin, a compound showing promising anticancer activity against prostate cancer cells. This compound may offer new therapeutic strategies for prostate malignancies by targeting CB1 receptors.
Area of Science:
- Natural Product Chemistry
- Mycology
- Cancer Biology
Background:
- Prostate cancer (PCa) is a leading global malignancy with significant challenges in treatment, particularly castration-resistant prostate cancer (CRPCa).
- Existing therapies for advanced PCa face limitations due to toxicity, efficacy, and resistance.
- Novel therapeutic agents are urgently needed to combat aggressive and metastatic prostate cancer phenotypes.
Purpose of the Study:
- To isolate and identify bioactive compounds from the soil-derived fungus Aspergillus neoniveus.
- To evaluate the in vitro anticancer potential of fungal extracts and isolated metabolites against various prostate cancer cell lines.
- To elucidate the molecular mechanism underlying the anticancer activity of key compounds, focusing on potential therapeutic targets.
Main Methods:
- Genotypic identification of Aspergillus neoniveus using PCR-based internal transcribed spacer (ITS) region amplification.
- Metabolomic profiling of fungal extracts using High-Performance Liquid Chromatography/Mass Spectrometry (HPLC/MS).
- Isolation and structural elucidation of compounds via extensive spectral analysis (NMR, MS) and X-ray crystallography.
- In vitro screening of antiproliferative and anti-migratory activities against human prostate cancer cell lines.
- Computational target prediction, molecular modeling, and docking studies to identify potential biological targets.
Main Results:
- Forty-five compounds were tentatively identified from Aspergillus neoniveus, including novel compounds nervonic acid methyl ester, acetyl aszonalenin, and butyrolactone II.
- The fungal extract and isolated metabolites demonstrated significant in vitro antiproliferative and anti-migratory effects on multiple prostate cancer cell lines, including CRPCa models.
- Acetyl aszonalenin was identified as a key bioactive compound with promising anticancer properties.
- Computational analyses predicted the cannabinoid G-protein coupled receptor type 1 (CB1) as a potential target for acetyl aszonalenin's anticancer effects, supported by favorable molecular docking results.
Conclusions:
- Aspergillus neoniveus is a source of diverse bioactive natural products with potential anticancer applications.
- Acetyl aszonalenin exhibits significant in vitro anticancer activity against prostate cancer cells, including castration-resistant phenotypes.
- Modulation of CB1 receptors by acetyl aszonalenin presents a promising therapeutic strategy for prostate cancer treatment, warranting further investigation and optimization.
