title: Flavokawain derivative FLS induced G2/M arrest and apoptosis on breast cancer MCF-7 cell line.
abstract: Known as naturally occurring biologically active compounds, flavokawain A and B are the leading chalcones that possess anticancer properties. Another flavokawain derivative, (E)-1-(2'-Hydroxy-4',6'-dimethoxyphenyl)-3-(4-methylthio)phenyl)prop-2-ene-1-one (FLS) was characterized with (1)H-nuclear magnetic resonance, electron-impact mas spectrometry, infrared spectroscopy, and ultraviolet ((1)H NMR, EI-MS, IR, and UV) spectroscopic techniques. FLS cytotoxic efficacy against human cancer cells (MCF-7, MDA-MB-231, and MCF-10A) resulted in the reduction of IC50 values in a time- and dose-dependent mode with high specificity on MCF-7 (IC50 of 36 μM at 48 hours) against normal breast cell MCF-10A (no IC50 detected up to 180 μM at 72 hours). Light, scanning electron, and fluorescent microscopic analysis of MCF-7 cells treated with 36 μM of FLS displayed cell shrinkage, apoptotic body, and DNA fragmentation. Additionally, induction of G2/M cell arrest within 24 hours and apoptosis at subsequent time points was discovered via flow cytometry analysis. The roles of PLK-1, Wee-1, and phosphorylation of CDC-2 in G2/M arrest and proapoptotic factors (Bax, caspase 9, and p53) in promotion of apoptosis of FLS against MCF-7 cells were discovered using fluorometric, quantitative real-time polymerase chain reaction, and Western blot analysis. Interestingly, the presence of SCH3 (thiomethyl group) on ring B structure contributed to the selective cytotoxicity against MCF-7 cells compared to other chalcones, flavokawain A and B. Overall, our data suggest potential therapeutic value for flavokawain derivative FLS to be further developed as a new anticancer drug.
authors.affiliation: Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia.
authors.forename: Norlaily Mohd
authors.initials: NM
authors.lastname: Ali
authors.affiliation: Department of Industrial Biotechnology, Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Pahang, Malaysia.
authors.forename: M Nadeem
authors.initials: MN
authors.lastname: Akhtar
authors.affiliation: Department of Agriculture Genetics and Breeding, College of Agriculture and Applied Biology, Cantho University, CanTho City, Vietnam.
authors.forename: Huynh
authors.initials: H
authors.lastname: Ky
authors.affiliation: Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia.
authors.forename: Kian Lam
authors.initials: KL
authors.lastname: Lim
authors.affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor, Malaysia.
authors.forename: Nadiah
authors.initials: N
authors.lastname: Abu
authors.affiliation: Department of Industrial Biotechnology, Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Pahang, Malaysia.
authors.forename: Seema
authors.initials: S
authors.lastname: Zareen
authors.affiliation: School of Biomedical Sciences, The University of Nottingham Malaysia Campus, Selangor, Malaysia.
authors.forename: Wan Yong
authors.initials: WY
authors.lastname: Ho
authors.affiliation: Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia.
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Alan-Ong
authors.affiliation: Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia.
authors.forename: Sheau Wei
authors.initials: SW
authors.lastname: Tan
authors.affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor, Malaysia.
authors.forename: Noorjahan Banu
authors.initials: NB
authors.lastname: Alitheen
authors.affiliation: Department of Industrial Biotechnology, Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Pahang, Malaysia.
authors.forename: Jamil Bin
authors.initials: JB
authors.lastname: Ismail
authors.affiliation: Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia.
authors.forename: Swee Keong
authors.initials: SK
authors.lastname: Yeap
authors.affiliation: Tissue Engineering Group, National Orthopaedic Centre of Excellence for Research and Learning, Department of Orthopaedic Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia.
authors.forename: Tunku
authors.initials: T
authors.lastname: Kamarul
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000617911:(E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(4-methylthio)phenyl)prop-2-ene-1-one; D000970:Antineoplastic Agents; D013438:Sulfhydryl Compounds
keywords: (E)-1-(2′-Hydroxy-4′,6′-dimethoxyphenyl)-3-(4-methylthio)phenyl)prop-2-ene-1-one (FLS); G2/M arrest; MCF-7; PLK-1; apoptosis; caspase; cell cycle; p53