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

Mohamed S. Mady, Mohamed M. Mohyeldin, Hassan Y. Ebrahim, Heba E. Elsayed, Wael E. Houssen, Eman G. Haggag, Randa F. Soliman, Khalid A. El Sayed*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)113-122
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number2
DOIs
Publication statusPublished - 15 Jan 2016

Bibliographical note

Funding Information:
The Egyptian Ministry of Higher Education is acknowledged for supporting M.S.M.’s fellowship. Research reported in this publication was supported in-part by the National Cancer Institute of the National Institutes of Health under Award Number R15CA167475-01.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

  • Bioassay-guided
  • Breast cancer
  • c-Met
  • Endophyte
  • Meleagrin
  • Olive tree
  • Penicillum chrysogenum

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