title: 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.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, United States; Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Helwan, Cairo 11795, Egypt.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Mady
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, United States.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Mohyeldin
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, United States.
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Ebrahim
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, United States.
authors.forename: Heba E
authors.initials: HE
authors.lastname: Elsayed
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK; Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Wael E
authors.initials: WE
authors.lastname: Houssen
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Helwan, Cairo 11795, Egypt.
authors.forename: Eman G
authors.initials: EG
authors.lastname: Haggag
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Helwan, Cairo 11795, Egypt.
authors.forename: Randa F
authors.initials: RF
authors.lastname: Soliman
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, United States. Electronic address: elsayed@ulm.edu.
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009361:Neoplasm Invasiveness / Q000473:pathology; D031658:Olea / Q000382:microbiology*; D010059:Ovomucin / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010408:Penicillium chrysogenum / Q000737:chemistry*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D026121:Indole Alkaloids; D010059:Ovomucin; C060672:meleagrin; D019859:Proto-Oncogene Proteins c-met
keywords: Bioassay-guided; Breast cancer; Endophyte; Meleagrin; Olive tree; Penicillum chrysogenum; c-Met