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Bioprocessing of monomethyl ether from Alternaria alternata, a multi-target antiproliferative compound as emphasized
Suhaila R Alsaid1,2,3, Manar M Abdel Gwad1, Gamal Abdel-Fattah1
1Botany and Microbiology Department, Faculty of Science, Mansoura University, Mansoura, Egypt.
Abstract:
The emergence of drug-resistant cancer cells driven by mutations, proteins tertiary structure alterations, and overexpression of drug efflux pumps, particularly P-glycoprotein (P-gp) system is the major challenge of cancer chemotherapy. Consequently, the search for affordable, stable, and multi-targeted lead compounds has become a critical objective. Alternariol monomethyl ether (AME) is known for its cytotoxic activity; nevertheless, its bioavailability and in vivo efficacy remains equivocal, which limits its further therapeutic application. Alternaria alternata LSR PV576354.1, inhabiting stored barely seeds, was isolated with the highest yields of AOH and AME as quantified by HPLC. Upon nutritional bioprocessing, the yield of AOH and AME by A. alternata was increased to 8.65 µg/ml and 10.05 µg/ml, respectively, at C:N ratio 14.2:1, of pH 5.0 after 18 days. The purified AME of A. alternata was chemically resolved from the HPLC, LC-MS and MS/MS analyses, with 272.2 m/z, and consistent fragmentation pattern of authentic AME. The maximum antiproliferative activity of AME was reported for HCT-116 (0.61 μg/ml), HepG-2 (1.72 μg/ml), MCF-7 cells (2.41 μg/ml), with selectivity indices 17.1, 6.4, 4.3 folds, compared to normal OEC cells. AME of A. alternata had a strong anti-tubulin polymerizing activity (IC50 value 3.9 μg/ml), anti- topoisomerase I (IC50 value 40.9 μg/ml) and II (IC50 value 35.6 μg/ml) activities. The AME of A. alternata strongly induces the total, early apoptosis, late apoptosis and necrosis of the HCT-116 cells by 6.7, 19.5, 17.2 and 1.8 folds, compared to the control cells. From the molecular docking analysis, the AME of A. alternata had a conceivable binding energies with topoisomerase I, II and β-tubulin (-7.0-7.3 kcal/mol), with RMSD values 1.5 and 1.9Å, respectively. Consequently, from the experimental and in silico analyses, A. alternata AME could be a promising multi-target antiproliferative lead compound, and with further structure-activity relationship, transcriptomics and proteomics analyses, this compound could be a novel platform of cancer chemotherapy.
Insights
This study enhances Alternaria alternata
Area of Science:
- Biochemistry
- Molecular Biology
- Mycology
Background:
- Drug-resistant cancer poses a significant challenge in chemotherapy.
- P-glycoprotein (P-gp) overexpression contributes to multidrug resistance.
- There is a critical need for novel, multi-targeted anticancer compounds.
Purpose of the Study:
- To optimize the production of Alternariol monomethyl ether (AME) from Alternaria alternata.
- To evaluate the antiproliferative and mechanistic activities of AME against cancer cells.
- To investigate the potential of AME as a multi-target lead compound for cancer chemotherapy.
Main Methods:
- Nutritional bioprocessing of A. alternata to increase AME yield.
- High-Performance Liquid Chromatography (HPLC), Liquid Chromatography-Mass Spectrometry (LC-MS), and Mass Spectrometry/Mass Spectrometry (MS/MS) for AME purification and identification.
- In vitro antiproliferative assays against various cancer cell lines (HCT-116, HepG-2, MCF-7) and normal cells (OEC).
- Assays for anti-tubulin polymerization, topoisomerase I and II inhibition, and apoptosis induction.
- Molecular docking simulations to assess binding affinities with target proteins (topoisomerase I, II, and β-tubulin).
Main Results:
- Optimized bioprocessing significantly increased AME yield (up to 10.05 μg/ml).
- Purified AME demonstrated potent antiproliferative activity against HCT-116, HepG-2, and MCF-7 cells with notable selectivity indices.
- AME exhibited strong inhibition of tubulin polymerization and topoisomerase I/II activity.
- AME effectively induced apoptosis and necrosis in HCT-116 cells.
- Molecular docking revealed favorable binding energies between AME and target proteins.
Conclusions:
- Alternaria alternata is a viable source for producing AME with enhanced yields through bioprocessing.
- AME displays significant multi-targeted anticancer properties, including antiproliferative, anti-tubulin, and topoisomerase inhibitory activities.
- AME induces apoptosis in cancer cells and shows promising binding interactions with key cancer-related proteins.
- AME represents a potential novel platform for developing multi-target cancer chemotherapy agents, warranting further investigation into structure-activity relationships and molecular mechanisms.
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