The indole alkaloid meleagrin, from the olive tree endophytic fungus Penicillium chrysogenum, as a novel lead for the control of c-Met-dependent breast cancer proliferation, migration and invasion

Abstract

Fungi of the genus Penicillium produce unique and chemically diverse biologically active secondary metabolites, including indole alkaloids. The role of dysregulated hepatocyte growth factor (HGF) and its receptor, c-Met, in the development and progression of breast carcinoma is documented. The goal of this work is to explore the chemistry and bioactivity of the secondary metabolites of the endophytic Penicillium chrysogenum cultured from the leaf of the olive tree Olea europea, collected in its natural habitat in Egypt. This fungal extract showed good inhibitory activities against the proliferation and migration of several human breast cancer lines. The CH2Cl2 extract of P. chrysogenum mycelia was subjected to bioguided chromatographic separation to afford three known indole alkaloids; meleagrin (1), roquefortine C (2) and DHTD (3). Meleagrin inhibited the growth of the human breast cancer cell lines MDA-MB-231, MDA-468, BT-474, SK BR-3, MCF7 and MCF7-dox, while similar treatment doses were found to have no effect on the growth and viability of the non-tumorigenic human mammary epithelial cells MCF10A. Meleagrin also showed excellent ATP competitive c-Met inhibitory activity in Z-Lyte assay, which was further confirmed via molecular docking studies and Western blot analysis. In addition, meleagrin treatment caused a dose-dependent inhibition of HGF-induced cell migration, and invasion of breast cancer cell lines. Meleagrin treatment potently suppressed the invasive triple negative breast tumor cell growth in an orthotopic athymic nude mice model, promoting this unique natural product from hit to a lead rank. The indole alkaloid meleagrin is a novel lead c-Met inhibitory entity useful for the control of c-Met-dependent metastatic and invasive breast malignancies.

Deletion of the Histone Deacetylase HdaA in Endophytic Fungus Penicillium chrysogenum Fes1701 Induces the Complex Response of Multiple Bioactive Secondary Metabolite Production and Relevant Gene Cluster Expression

“…Meleagrin (2) exhibited the best growth-inhibitory activity against two different leukemia cells (K562 and HL-60) with IC 50 values of 8.9 and 12.7 μM. A similar level of antineoplastic activity was reported by Mady et al [ 38 ], in which meleagrin (2) showed significant inhibitory activities against the proliferation and migration of c-Met-dependent breast malignancy. Roquefortine alkaloids (3,4) showed a medium antibacterial activity against Gram-negative bacterium Escherichia coli and Gram-positive bacterium Staphylococcus aureus .…”

Nigrospora sphaerica products from the flowering dogwood exhibit antitumorigenic effects via the translational regulator, pS6 ribosomal protein

“…Since tumor recurrence is a manifestation of the resistance of many cancers to clinically used chemotherapeutic agents, we next examined the efficacy of N. sphaerica crude extracts to inhibit lung cancer and glioblastoma cell migration. Boyden chamber assays revealed that cells treated with 2 µg/ml of N. sphaerica crude extracts decreased (P < 0.05) tumor cell migration as compared to vehicle-treated control cells [ Figure 7], paralleling recent findings by Mady et al [22] that showed the endophytic fungus Penicillium chrysogenum impaired breast cancer cell migration.…”

OxaD: A Versatile Indolic Nitrone Synthase from the Marine-Derived Fungus Penicillium oxalicum F30

“…78 By coupling this derivatization strategy with the broad substrate scope of OxaD, we have established a platform in which novel indole alkaloid frameworks can be paired with an array of dipolarophiles in a cycloaddition cascade. Recent reports describing the therapeutic potential of 2 29 and 3 27,30 provide strong motivation to develop these tools. Future efforts in our laboratories will also seek to extend the substrate scope of OxaD beyond alkaloids in the roquefortine family.…”