title: (6E,10E) Isopolycerasoidol and (6E,10E) Isopolycerasoidol Methyl Ester, Prenylated Benzopyran Derivatives from Pseuduvaria monticola Induce Mitochondrial-Mediated Apoptosis in Human Breast Adenocarcinoma Cells.
abstract: Phytochemicals from Pseuduvaria species have been reported to display a wide range of biological activities. In the present study, a known benzopyran derivative, (6E,10E) isopolycerasoidol (1), and a new benzopyran derivative, (6E,10E) isopolycerasoidol methyl ester (2), were isolated from a methanol extract of Pseuduvaria monticola leaves. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR, IR, UV, and LCMS-QTOF, and by comparison with previously published data. The anti-proliferative and cytotoxic effects of these compounds on human breast cancer cell-lines (MCF-7 and MDA-MB-231) and a human normal breast epithelial cell line (MCF-10A) were investigated. MTT results revealed both (1) and (2) were efficient in reducing cell viability of breast cancer cells. Flow cytometry analysis demonstrated that (1) and (2) induced cell death via apoptosis, as demonstrated by an increase in phosphotidylserine exposure. Both compounds elevated ROS production, leading to reduced mitochondrial membrane potential and increased plasma membrane permeability in breast cancer cells. These effects occurred concomitantly with a dose-dependent activation of caspase 3/7 and 9, a down-regulation of the anti-apoptotic gene BCL2 and the accumulation of p38 MAPK in the nucleus. Taken together, our data demonstrate that (1) and (2) induce intrinsic mitochondrial-mediated apoptosis in human breast cancer cells, which provides the first pharmacological evidence for their future development as anticancer agents.
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Hairin
authors.initials: H
authors.lastname: Taha
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Chung Yeng
authors.initials: CY
authors.lastname: Looi
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Aditya
authors.initials: A
authors.lastname: Arya
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Won Fen
authors.initials: WF
authors.lastname: Wong
authors.affiliation: Department of Oral Biology and Biomedical Sciences, and Oral Cancer Research and Coordinating Centre (OCRCC),Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Lee Fah
authors.initials: LF
authors.lastname: Yap
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Mohadeseh
authors.initials: M
authors.lastname: Hasanpourghadi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Mohd
authors.affiliation: Department of Oral Biology and Biomedical Sciences, and Oral Cancer Research and Coordinating Centre (OCRCC),Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Paterson
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Hapipah
authors.initials: H
authors.lastname: Mohd Ali
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D029061:Annonaceae / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000606813:(6E,10E)isopolycerasoidol; C000606814:(6E,10E)isopolycerasoidol methyl ester; D000972:Antineoplastic Agents, Phytogenic; D001578:Benzopyrans; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases