title: Marine natural products-inspired phenylmethylene hydantoins with potent in vitro and in vivo antitumor activities via suppression of Brk and FAK signaling.
abstract: Breast and prostate cancers are among the most common cancers worldwide with devastating statistics for the metastatic, chemotherapy- and radiotherapy-resistant phenotypes. Novel therapies interfering with new and/or multiple pathways involved in the pathology of cancer are urgently needed. Preliminary results showed that the marine natural product Z-4-hydroxyphenylmethylene hydantoin (PMH, ) and its 4-ethylthio-analog (SEth, ) promoted tight junction formation and showed anti-invasive and anti-migratory activities in vitro against metastatic prostate cancer cells and inhibited tumor growth and micrometastases in distant organs in orthotopic and transgenic mice models. This study focuses on the design and synthesis of second-generation PMHs with enhanced antitumor activities. A series of substituted benzaldehydes was selected based on earlier SAR studies and reacted with hydantoin to yield 11 new compounds . Compounds were evaluated for their antiproliferative, antimigratory and anti-invasive properties in vitro against the human mammary and prostate cancer cell lines MDA-MB-231 and PC-3, respectively. A Western blot analysis of the most active analog showed its ability to suppress the expression of the total levels of c-Met and FAK, with subsequent reduction of their phosphorylated (activated) levels in MDA-MB-231 cells. In addition, also inhibited Brk, paxillin and Rac1 phosphorylation. was formulated using hydroxypropyl β-cyclodextrin (HPCD) to improve its solubility and was further evaluated in a nude mice xenograft model using MDA-MB-231/GFP cells. PMH reduced breast tumor growth and suppressed Ki-67, CD31, p-Brk and p-FAK expression in tumor samples. Thus, is a potential lead for the control of invasive breast malignancies.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana 71201, USA. elsayed@ulm.edu.
authors.forename: Asmaa A
authors.initials: AA
authors.lastname: Sallam
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Mohyeldin
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Foudah
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Akl
authors.forename: Sami
authors.initials: S
authors.lastname: Nazzal
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Meyer
authors.forename: Yong-Yu
authors.initials: YY
authors.lastname: Liu
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001547:Benzaldehydes / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006827:Hydantoins / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051419:Paxillin / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000597345:(Z)-5-((4'-Fluorobiphenyl-10-yl)methylene)imidazolidine-2,4-dione; D000970:Antineoplastic Agents; D001547:Benzaldehydes; D001688:Biological Products; D006827:Hydantoins; D009363:Neoplasm Proteins; C496061:PXN protein, human; D051419:Paxillin; C107953:RAC1 protein, human; D011505:Protein-Tyrosine Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C088375:PTK6 protein, human; D020830:rac1 GTP-Binding Protein