title: Cycloart-24-ene-26-ol-3-one, a New Cycloartane Isolated from Leaves of Aglaia exima Triggers Tumour Necrosis Factor-Receptor 1-Mediated Caspase-Dependent Apoptosis in Colon Cancer Cell Line.
abstract: Plants in the Meliaceae family are known to possess interesting biological activities, such as antimalaral, antihypertensive and antitumour activities. Previously, our group reported the plant-derived compound cycloart-24-ene-26-ol-3-one isolated from the hexane extracts of Aglaia exima leaves, which shows cytotoxicity towards various cancer cell lines, in particular, colon cancer cell lines. In this report, we further demonstrate that cycloart-24-ene-26-ol-3-one, from here forth known as cycloartane, reduces the viability of the colon cancer cell lines HT-29 and CaCO-2 in a dose- and time-dependent manner. Further elucidation of the compound's mechanism showed that it binds to tumour necrosis factor-receptor 1 (TNF-R1) leading to the initiation of caspase-8 and, through the activation of Bid, in the activation of caspase-9. This activity causes a reduction in mitochondrial membrane potential (MMP) and the release of cytochrome-C. The activation of caspase-8 and -9 both act to commit the cancer cells to apoptosis through downstream caspase-3/7 activation, PARP cleavage and the lack of NFkB translocation into the nucleus. A molecular docking study showed that the cycloartane binds to the receptor through a hydrophobic interaction with cysteine-96 and hydrogen bonds with lysine-75 and -132. The results show that further development of the cycloartane as an anti-cancer drug is worthwhile.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.|Center for Natural Product and Drug Discovery (CENAR), Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Kok Hoong
authors.identifier: http://orcid.org/0000-0002-7317-6117
authors.initials: KH
authors.lastname: Leong
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 Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Xe-Min
authors.initials: XM
authors.lastname: Loong
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Foo Kit
authors.initials: FK
authors.lastname: Cheah
authors.affiliation: Department of Chemistry, Faculty of Mathematics and Natural Sciences, Padjadjaran University, Jatinangor, Indonesia.
authors.forename: Unang
authors.initials: U
authors.lastname: Supratman
authors.affiliation: Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS 1, Avenue de la Terrasse, Gif-sur-Yvette Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Litaudon
authors.affiliation: Center for Natural Product and Drug Discovery (CENAR), Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.|Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Mohd Rais
authors.initials: MR
authors.lastname: Mustafa
authors.affiliation: Center for Natural Product and Drug Discovery (CENAR), Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.|Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Khalijah
authors.initials: K
authors.lastname: Awang
mesh_terms: D031602:Aglaia / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018515:Plant Leaves / Q000737:chemistry*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D014315:Triterpenes; C085352:cycloartane; D045304:Cytochromes c; D020169:Caspases