title: Antioxidative activity of diarylheptanoids from the bark of black alder (Alnus glutinosa) and their interaction with anticancer drugs.
abstract: Diarylheptanoids belong to polyphenols, a group of plant secondary metabolites with multiple biological properties. Many of them display antioxidative, cytotoxic, or anticancer actions and are increasingly recognized as potential therapeutic agents. The aim of this study was to evaluate antioxidant and cytoprotective activity of two diarylheptanoids: platyphylloside 5(S)-1,7-di(4-hydroxyphenyl)-3-heptanone-5-O-β-D-glucopyranoside (1) and its newly discovered analog 5(S)-1,7-di(4-hydroxyphenyl)-5-O-β-D-[6-(E-p-coumaroylglucopyranosyl)]heptane-3-one (2), both isolated from the bark of black alder (Alnus glutinosa). To that end, we have employed a cancer cell line (NCI-H460), normal human keratinocytes (HaCaT), and peripheral blood mononuclear cells. The effects on cell growth were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Cell death was examined by annexin V/propidium iodide staining on a flow cytometer. Reactive oxygen species production was examined by dihydroethidium staining. Mitochondrial structure and doxorubicin localization were visualized by fluorescent microscopy. Gene expression of manganese superoxide dismutase and hypoxia-inducible factor-1α was determined by reverse transcription polymerase chain reaction. Diarylheptanoids antagonized the effects of either doxorubicin or cisplatin, significantly increasing their IC50 values in normal cells. Diarylheptanoid 1 induced the retention of doxorubicin in cytoplasm and reduced mitochondrial fragmentation associated with doxorubicin application. Diarylheptanoid 2 reduced the reactive oxygen species production induced by cisplatin. Both compounds increased the messenger ribonucleic acid expression of enzymes involved in reactive oxygen species elimination (manganese superoxide dismutase and hypoxia-inducible factor-1α). These results indicate that neutralization of reactive oxygen species is an important mechanism of diarylheptanoid action, although these compounds exert a considerable anticancer effect. Therefore, these compounds may serve as protectors of normal cells during chemotherapy without significantly diminishing the effect of the applied chemotherapeutic.
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Dinić
authors.affiliation: Institute for Chemistry, Technology and Metallurgy, University of Belgrade, Belgrade, Serbia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Novaković
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Podolski-Renić
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Belgrade, Serbia.
authors.forename: Sonja
authors.initials: S
authors.lastname: Stojković
authors.affiliation: Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Boris
authors.initials: B
authors.lastname: Mandić
authors.affiliation: Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Vele
authors.initials: V
authors.lastname: Tešević
authors.affiliation: Institute for Chemistry, Technology and Metallurgy, University of Belgrade, Belgrade, Serbia.
authors.forename: Vlatka
authors.initials: V
authors.lastname: Vajs
authors.affiliation: Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Isaković
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Pešić
mesh_terms: D029661:Alnus / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D036381:Diarylheptanoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004317:Doxorubicin / Q000032:analysis / Q000378:metabolism; D041743:Herb-Drug Interactions; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D024301:Plant Bark / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D036381:Diarylheptanoids; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D013482:Superoxide Dismutase