title: Indole diterpene alkaloids as novel inhibitors of the Wnt/β-catenin pathway in breast cancer cells.
abstract: Penitrems are indole diterpene alkaloids best known for their BK channel inhibition and tremorgenic effects in mammals. In a previous study, penitrems A-F (1-5), their biosynthetic precursors, paspaline (6) and emindole SB (7), and two brominated penitrem analogs 8 and 9 demonstrated promising in vitro antiproliferative, antimigratory, and anti-invasive effects in the MTT (MCF-7 and MDA-MB-231), wound-healing, and Cultrex BME cell invasion (MDA-MB-231) assays, respectively. The study herein reports the novel ability of penitrem A to suppress total β-catenin levels in MDA-MB-231 mammary cancer cells. Nine new penitrem analogs (10-18) were semisynthetically prepared, in an attempt to identify pharmacophores correlated with BK channel inhibition and tremorgenicity of penitrems and decrease their toxicity. The degree of BK channel inhibition was assessed using the nematode Caenorhabditis elegans, and in vivo tremorgenic EC₅₀ was calculated using CD-1 male mice following an Up-and-Down Procedure (UDP). Although new analogs were generally less active than parent compound 1, some showed no BK channel inhibition or tremorgenicity and retained the ability of penitrem A (1) to suppress total β-catenin levels in MDA-MB-231 cells. Paspaline (6) and emindole SB (7), both lacking BK channel inhibition and tremorgenicity, represent the simplest indole diterpene skeleton that retains the antiproliferative, antimigratory and total β-catenin suppressing effects shown by the more complex penitrem A (1).
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, USA.
authors.forename: Asmaa A
authors.initials: AA
authors.lastname: Sallam
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Ayoub
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Foudah
authors.forename: Chris R
authors.initials: CR
authors.lastname: Gissendanner
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Meyer
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*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009183:Mycotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D026121:Indole Alkaloids; D009183:Mycotoxins; D051153:Wnt Proteins; D051176:beta Catenin; C003626:tremortin
keywords: Antimigratory; Antiproliferative; BK channel inhibition; Breast cancer; Caenorhabditis elegans; Invasion; Penitrems; Wnt/β-catenin pathway