title: Norstictic Acid Inhibits Breast Cancer Cell Proliferation, Migration, Invasion, and In Vivo Invasive Growth Through Targeting C-Met.
abstract: Breast cancer is a major health problem affecting the female population worldwide. The triple-negative breast cancers (TNBCs) are characterized by malignant phenotypes, worse patient outcomes, poorest prognosis, and highest mortality rates. The proto-oncogenic receptor tyrosine kinase c-Met is usually dysregulated in TNBCs, contributing to their oncogenesis, tumor progression, and aggressive cellular invasiveness that is strongly linked to tumor metastasis. Therefore, c-Met is proposed as a promising candidate target for the control of TNBCs. Lichens-derived metabolites are characterized by their structural diversity, complexity, and novelty. The chemical space of lichen-derived metabolites has been extensively investigated, albeit their biological space is still not fully explored. The anticancer-guided fractionation of Usnea strigosa (Ach.) lichen extract led to the identification of the depsidone-derived norstictic acid as a novel bioactive hit against breast cancer cell lines. Norstictic acid significantly suppressed the TNBC MDA-MB-231 cell proliferation, migration, and invasion, with minimal toxicity to non-tumorigenic MCF-10A mammary epithelial cells. Molecular modeling, Z'-LYTE biochemical kinase assay and Western blot analysis identified c-Met as a potential macromolecular target. Norstictic acid treatment significantly suppressed MDA-MB-231/GFP tumor growth of a breast cancer xenograft model in athymic nude mice. Lichen-derived natural products are promising resources to discover novel c-Met inhibitors useful to control TNBCs.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, 71201, USA.
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, Monroe, Louisiana, 71201, USA.
authors.forename: Heba E
authors.initials: HE
authors.lastname: Elsayed
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, 71201, USA.
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, Monroe, Louisiana, 71201, USA.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Akl
authors.affiliation: Department of Biology, School of Sciences, University of Louisiana at Monroe, Monroe, Louisiana, 71201, USA.
authors.forename: Joydeep
authors.initials: J
authors.lastname: Bhattacharjee
authors.affiliation: Department of Biology, School of Sciences, University of Louisiana at Monroe, Monroe, Louisiana, 71201, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Egbert
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, 71201, USA.
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D020949:Usnea / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007783:Lactones; D012459:Salicylates; C553078:norstictic acid; D019859:Proto-Oncogene Proteins c-met
keywords: TNBC; Usnea; breast cancer; c-Met; lichen; norstictic acid