title: New halogenated constituents from Mangifera zeylanica Hook.f. and their potential anti-cancer effects in breast and ovarian cancer cells.
abstract: BACKGROUND
  Mangifera zeylanica Hook.f. (Anacardiaceae) is a plant endemic to Sri Lanka. Its bark has been used in traditional and Ayurvedic medicine for the treatment of various diseases including some cancers.
  
  
  OBJECTIVE
  This study was planned to isolate and identify potentially cytotoxic compounds from the bark of M. zeylanica, which may have contributed to its ethno pharmacological use in the treatment of cancer.
  
  
  METHODS
  The chloroform extract of M. zeylanica bark which is cytotoxic to breast and ovarian cancer cells was fractionated using column chromatography and preparative reversed phase high performance liquid chromatography to isolate four compounds. Structures of the isolated compounds were elucidated by means of (1)H- and (13)C NMR spectroscopy, and mass spectrometric techniques. Cytotoxic potential of the isolated compounds was tested in MDA-MB-231 (triple negative breast cancer), MCF-7 (estrogen receptor positive breast cancer), SKOV-3 (ovarian epithelial cancer) and MCF-10A (normal mammary epithelial) cells by SRB assay. Human cancer drug target real-time PCR array was carried out to analyze regulation of possible cancer drug target genes in compound 2 treated triple negative breast cancer cells. DPPH radical scavenging and caspase 3 and 7 induction in response to isolated compounds were also studied.
  
  
  RESULTS
  Two new halogenated compounds, bromomangiferic acid (1), and chloromangiferamide (2) along with two known compounds quercetin (3), and catechin (4), were isolated from the bark of Mangifera zeylanica for the first time. Interestingly, chloromangiferamide showed cytotoxicity only to triple negative breast cancer cells [IC50:73.19±0.87µM (24h), 56.29±0.86µM (48h)] with no cytotoxicity to other two cancer cell lines or to normal mammary epithelial cells. Quercetin and catechin were cytotoxic to all three cancer cell lines while bromomangiferic acid had no effect. Chloromangiferamide significantly regulated expression of genes associated with apoptosis, drug metabolism, cell cycle, receptor tyrosine kinase signaling, protein kinases, histone deacetylases, growth factors and receptors, topoisomerases, PI-3 kinases and phosphatases in triple negative breast cancer cells.
  
  
  CONCLUSIONS
  Selective cytotoxic activity in triple negative breast cancer cells and regulation of some cancer drug target genes by chloromangiferamide indicate that it can be used to develop a potential chemotherapeutic agent for triple negative breast cancer cells.
authors.affiliation: Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka. Electronic address: mk.ediriweera@gmail.com.
authors.forename: Meran Keshawa
authors.initials: MK
authors.lastname: Ediriweera
authors.affiliation: Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka. Electronic address: kamani@ibmbb.cmb.ac.lk.
authors.forename: Kamani Hemamala
authors.initials: KH
authors.lastname: Tennekoon
authors.affiliation: International Center for Chemical and Biological Sciences, HEJ Research Institute of Chemistry, University of Karachi, Pakistan. Electronic address: adhikarimine@yahoo.com.
authors.forename: Achyut
authors.initials: A
authors.lastname: Adhikari
authors.affiliation: Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka. Electronic address: sam@ibmbb.cmb.ac.lk.
authors.forename: Sameera Ranganath
authors.initials: SR
authors.lastname: Samarakoon
authors.affiliation: Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka. Electronic address: irathab@gmail.com.
authors.forename: Ira
authors.initials: I
authors.lastname: Thabrew
authors.affiliation: Department of Chemistry, Faculty of Science, University of Colombo, Colombo 3, Sri Lanka. Electronic address: edilip.desilva@gmail.com.
authors.forename: E Dilip
authors.initials: ED
authors.lastname: de Silva
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002725:Chloroform / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D054879:Halogenation; D006801:Humans; D061986:MCF-7 Cells; D031022:Mangifera / Q000737:chemistry*; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008517:Phytotherapy; D024301:Plant Bark / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D066244:Proton Magnetic Resonance Spectroscopy; D015398:Signal Transduction / Q000187:drug effects; D012997:Solvents / Q000737:chemistry; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D010936:Plant Extracts; D012997:Solvents; D002725:Chloroform
keywords: Anacardiaceae; Bromomangiferic acid; Chloromangiferamide; Mangifera Zeylanica; Triple negative breast cancer