title: Subditine, a new monoterpenoid indole alkaloid from bark of Nauclea subdita (Korth.) Steud. induces apoptosis in human prostate cancer cells.
abstract: In this study, a new apoptotic monoterpenoid indole alkaloid, subditine (1), and four known compounds were isolated from the bark of Nauclea subdita. Complete (1)H- and (13)C- NMR data of the new compound were reported. The structures of isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS. All five compounds were screened for cytotoxic activities on LNCaP and PC-3 human prostate cancer cell-lines. Among the five compounds, the new alkaloid, subditine (1), demonstrated the most potent cell growth inhibition activity and selective against LNCaP with an IC50 of 12.24±0.19 µM and PC-3 with an IC50 of 13.97±0.32 µM, compared to RWPE human normal epithelial cell line (IC50 = 30.48±0.08 µM). Subditine (1) treatment induced apoptosis in LNCaP and PC-3 as evidenced by increased cell permeability, disruption of cytoskeletal structures and increased nuclear fragmentation. In addition, subditine (1) enhanced intracellular reactive oxygen species (ROS) production, as reflected by increased expression of glutathione reductase (GR) to scavenge damaging free radicals in both prostate cancer cell-lines. Excessive ROS could lead to disruption of mitochondrial membrane potential (MMP), release of cytochrome c and subsequent caspase 9, 3/7 activation. Further Western blot analyses showed subditine (1) induced down-regulation of Bcl-2 and Bcl-xl expression, whereas p53 was up-regulated in LNCaP (p53-wild-type), but not in PC-3 (p53-null). Overall, our data demonstrated that the new compound subditine (1) exerts anti-proliferative effect on LNCaP and PC-3 human prostate cancer cells through induction of apoptosis.
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Sook Yee
authors.initials: SY
authors.lastname: Liew
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 Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Mohammadjavad
authors.initials: M
authors.lastname: Paydar
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 Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Kok Hoong
authors.initials: KH
authors.lastname: Leong
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 Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Mohd Rais
authors.initials: MR
authors.lastname: Mustafa
authors.affiliation: Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Gif-sur-Yvette, Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Litaudon
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Khalijah
authors.initials: K
authors.lastname: Awang
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008954:Models, Biological; D024301:Plant Bark / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D054837:Quinolizidines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D026121:Indole Alkaloids; D007211:Indoles; D054837:Quinolizidines; D017382:Reactive Oxygen Species; D013729:Terpenes; C000592474:subditine; C030374:indole; D045304:Cytochromes c; D005980:Glutathione Reductase; D020169:Caspases