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<p>The emergence of chemotherapy resistance is one of the challenges in cancer therapy, for the adaptability of cells to shield the normal targets, and expressing of efflux pumps to the normal drugs. Thus, searching for lead compounds of multiple targets activity in tumor cells, from novel endophytic fungi of medicinal plants, could be a distinctive approach for cancer chemotherapy. <i>Cladosporium cladosporioides</i> EFBL-025<i>,</i> endophyte of <i>Strelitzia nicolai,</i> was recognized for the first time as a potential Alternariol monomethyl ether (AME) producer (700.1 μg/l). This isolate was morphologically, and molecularly identified based on the ITS with accession # PX463714. The chemical identity of AME of <i>C. cladosporioides</i> was committed from the FT-IR, HPLC and LC-MS/MS. The molecular mass of the parent molecule was 274.2 m/z, with the same molecular fragmentation pattern of authentic AME, as revealed from LC-MS/MS. AME has a significant activity against the A549 (IC<sub>50</sub> 0.65 μg/ml), HepG-2 (IC<sub>50</sub> 1.2 μg/ml), MCF-7 cells (IC<sub>50</sub> 2.7 μg/ml), with selectivity index 28.2, 14.5 and 8.1 folds, respectively, compared to the OEC cells (IC<sub>50</sub> 18.4 μg/ml). The activity of AME was a slightly higher than Taxol towards the tested cells by 1.8 folds. The purified AME has a higher inhibitory activity for Topoisomerase II (IC<sub>50</sub> value 5.7 μg/ml) and I (IC<sub>50</sub> value 7.25 μg/ml), compared to Etoposide (15.02 μg/ml) and Topotecan (27.27 μg/ml). The maximum arrest of the MCF-7 cells growth was observed at G0-G1 phase by 73.9 %, with a potency to induce the apoptosis by 12 folds compared to the control cells, suggesting the interference with the machinery of cellular growth and protein synthesis prior to DNA replication. Upon treatment of MCF-7 cells with AME, the healing activity was reduced by 12.5 % after 24. From the docking analysis, the binding energy of AME with the <i>αβ</i>-tubulin vinca site was -8.3 kcal/mol, compared to -7.4 kcal/mol for vinblastine. The AME binding affinities with Topoisomerase I, II<i>α</i> and II<i>β</i> were -7.3, -8.0, -8.3 kcal/mol, respectively, revealing the higher affinity for Topoisomerase II, as being consistent from the experimental analysis. Thus, this is the first reports exploring the metabolic potency of <i>C. cladosporioides</i> as AME producer, with the different cytotoxic insights.</p>

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Cladosporium cladosporioides, endophyte of Strelitzia nicolai, as a new producer of Alternariol monomethyl ether with a potential cytotoxic activity

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  • 发表日期：

    2026年1月12日

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  • Nourhan M. Farag,
  • Ashraf S. A. El-Sayed,
  • Eman Fikry,
  • Nora Tawfeek,
  • Azza M. El-Shafae,
  • Maher M. El-Domiaty

摘要

The emergence of chemotherapy resistance is one of the challenges in cancer therapy, for the adaptability of cells to shield the normal targets, and expressing of efflux pumps to the normal drugs. Thus, searching for lead compounds of multiple targets activity in tumor cells, from novel endophytic fungi of medicinal plants, could be a distinctive approach for cancer chemotherapy. Cladosporium cladosporioides EFBL-025, endophyte of Strelitzia nicolai, was recognized for the first time as a potential Alternariol monomethyl ether (AME) producer (700.1 μg/l). This isolate was morphologically, and molecularly identified based on the ITS with accession # PX463714. The chemical identity of AME of C. cladosporioides was committed from the FT-IR, HPLC and LC-MS/MS. The molecular mass of the parent molecule was 274.2 m/z, with the same molecular fragmentation pattern of authentic AME, as revealed from LC-MS/MS. AME has a significant activity against the A549 (IC50 0.65 μg/ml), HepG-2 (IC50 1.2 μg/ml), MCF-7 cells (IC50 2.7 μg/ml), with selectivity index 28.2, 14.5 and 8.1 folds, respectively, compared to the OEC cells (IC50 18.4 μg/ml). The activity of AME was a slightly higher than Taxol towards the tested cells by 1.8 folds. The purified AME has a higher inhibitory activity for Topoisomerase II (IC50 value 5.7 μg/ml) and I (IC50 value 7.25 μg/ml), compared to Etoposide (15.02 μg/ml) and Topotecan (27.27 μg/ml). The maximum arrest of the MCF-7 cells growth was observed at G0-G1 phase by 73.9 %, with a potency to induce the apoptosis by 12 folds compared to the control cells, suggesting the interference with the machinery of cellular growth and protein synthesis prior to DNA replication. Upon treatment of MCF-7 cells with AME, the healing activity was reduced by 12.5 % after 24. From the docking analysis, the binding energy of AME with the αβ-tubulin vinca site was -8.3 kcal/mol, compared to -7.4 kcal/mol for vinblastine. The AME binding affinities with Topoisomerase I, IIα and IIβ were -7.3, -8.0, -8.3 kcal/mol, respectively, revealing the higher affinity for Topoisomerase II, as being consistent from the experimental analysis. Thus, this is the first reports exploring the metabolic potency of C. cladosporioides as AME producer, with the different cytotoxic insights.