title: 1'S-1'-acetoxyeugenol acetate: a novel phenylpropanoid from Alpinia conchigera enhances the apoptotic effects of paclitaxel in MCF-7 cells through NF-κB inactivation.
abstract: In this study, the apoptotic mechanism and combinatorial chemotherapeutic effects of the cytotoxic phenylpropanoid compound 1'S-1'-acetoxyeugenol acetate (AEA), extracted from rhizomes of the Malaysian ethnomedicinal plant Alpinia conchigera Griff. (Zingiberaceae), on MCF-7 human breast cancer cells were investigated for the first time. Data from cytotoxic and apoptotic assays such as live and dead and poly-(ADP-ribose) polymerase cleavage assays indicated that AEA was able to induce apoptosis in MCF-7 cells, but not in normal human mammary epithelial cells. A microarray global gene expression analysis of MCF-7 cells, treated with AEA, suggested that the induction of tumor cell death through apoptosis was modulated through dysregulation of the nuclear factor-kappaB (NF-κB) pathway, as shown by the reduced expression of various κB-regulated gene targets. Consequent to this, western blot analysis of proteins corresponding to the NF-κB pathway indicated that AEA inhibited phosphorylation levels of the inhibitor of κB-kinase complex, resulting in the elimination of apoptotic resistance originating from NF-κB activation. This AEA-based apoptotic modulation was elucidated for the first time in this study, and gave rise to the proposal of an NF-κB model termed the 'Switching/Alternating Model.' In addition to this, AEA was also found to synergistically enhance the proapoptotic effects of paclitaxel, when used in combination with MCF-7 cells, presumably by a chemosensitizing role. Therefore, it was concluded that AEA isolated from the Malaysian tropical ginger (A. conchigera) served as a very promising candidate for further in-vivo development in animal models and in subsequent clinical trials involving patients with breast-related malignancies.
authors.affiliation: Department of Genetics and Molecular Biology, Institute of Biological Science, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia. lionelin_81@yahoo.com
authors.forename: Lionel Lian Aun
authors.initials: LL
authors.lastname: In
authors.forename: Mohamad Nurul
authors.initials: MN
authors.lastname: Azmi
authors.forename: Halijah
authors.initials: H
authors.lastname: Ibrahim
authors.forename: Khalijah
authors.initials: K
authors.lastname: Awang
authors.forename: Noor Hasima
authors.initials: NH
authors.lastname: Nagoor
mesh_terms: D032429:Alpinia / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects; D005054:Eugenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D046228:Microarray Analysis / Q000379:methods; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D027343:Rhizome / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D005054:Eugenol; C057996:1'-acetoxyeugenol; D011065:Poly(ADP-ribose) Polymerases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; D017239:Paclitaxel