Endophytic Aspergillus glaucus as a novel epothilone B producer: Antiproliferative activity and in silico analysis

Epothilones are among the most potent anticancer agents, particularly against drug-resistant tumors, owing to their high affinity for β-tubulin stabilization, inhibiting the microtubule disassembly, ultimately leading to cell cycle arrest. However, their limited natural availability has restricted broader clinical and industrial exploitation. Accordingly, this study aimed to screen novel fungal isolates with sustainable and high metabolic capacity for epothilone production. Aspergillus glaucus OR342865.1, an endophyte isolated from the palm tree Latania lontaroides, exhibited the highest epothilone productivity (240 µg/L) upon response surface methodology optimization. The chemical identity of the purified compound was resolved by different chromatographic and spectroscopic analyses, revealing a structural profile consistence with authentic epothilone B. The putative epothilone B displayed potent cytotoxic activity against HepG-2, MCF-7, and HCT-116 cell lines, with half-maximal inhibitory concentration (IC₅₀) values of 0.028, 0.034, and 0.13 µM, with selectivity indices 12.5, 10.3, and 2.7, respectively, relative to Vero cells. The anti-invasive assay demonstrates a significant suppression (35.5-40.2%) of migratory capacity in MCF-7 and HepG-2 cells following treatment, indicating antimetastatic potential. Cell cycle analysis revealed that epothilone treatment induced G1 phase arrest in HepG-2 cells, with a 55.03% increase compared to the control. The total and early apoptotic populations increased to 32.2% and 22.03%, respectively, while late apoptosis exhibited a 57.6-fold elevation relative to untreated cells. The biological productivity of A. glaucus for epothilone B was stably maintained for up to 6 months when preserved as a slope culture at 4 °C. Molecular docking analysis demonstrated that epothilone B exhibits coherent multitarget interactions with key oncogenic kinases, including SRC, EGFR, JAK2, PIK3CA, mTOR, and HSP90, in addition to binding the β-tubulin taxane site, highlighting its capacity to modulate multiple cancer-related signaling pathways. To our knowledge, this is the first report demonstrating the high metabolic potential of A. glaucus for epothilone B production, positioning this fungus as a promising platform for sustainable industrial-scale biosynthesis of this clinically valuable anticancer agent. KEY POINTS: • Aspergillus glaucus, an endophyte of Latania lontaroides, is a potential epothilone B producer. • The purified epothilone has plausible antiproliferative, apoptotic, and antimetastatic activities. • The epothilone had coherent multitarget interactions with key oncogenic kinases and β-tubulin taxane site.