title: Versatile antitumor potential of isoxanthohumol: Enhancement of paclitaxel activity in vivo.
abstract: Isoxanthohumol (IXN), a prenylated flavonoid from hops, exhibits diverse biological activities, e.g. antitumor, antiinflammatory, antioxidant and antiangiogenic. In this study, the effect of IXN is evaluated on two melanoma cell lines with dissimilar molecular background, B16 and A375. The treatment of both cell lines with IXN resulted in dose-dependent decrease of cell viability. Abolished viability was in correlation with changed morphology and loss of dividing potential indicating phenotypical alteration of both tested cell lines. While modified B16 cells underwent the process of non-classic differentiation followed by tyrosinase activity without enhancement of melanin content, inhibition of Notch 1, β-catenin and Oct-3/4 was observed in A375 cells indicating loss of their pluripotent characteristics. In parallel with this, distinct subpopulations in both cell cultures entered the process of programmed cell death-apoptosis in a caspase independent manner. The described changes in cultures upon exposure to IXN could be connected with the suppression of reactive oxygen (ROS) and nitrogen species (RNS) induced by the drug. Despite the differences in which IXN promoted modifications in the upper part of the PI3K/Akt and MEK-ERK signaling pathways between B16 and A375 cells, p70S6K and its target S6 protein in both types of melanoma cells, after transient activation, became inhibited. In addition to direct input of IXN on cell viability, this study for the first time shows that IXN strongly sensitizes melanoma cells to the treatment with paclitaxel in vivo, in concordance with data obtained in vitro on B16 cells as well as their highly invasive F10 subclone.
authors.affiliation: Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia. Electronic address: tamara_krajnovic@yahoo.com.
authors.forename: Tamara
authors.initials: T
authors.lastname: Krajnović
authors.affiliation: Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, Halle (Saale), D 06120 Halle, Germany. Electronic address: goran.kaluderovic@ipb-halle.de.
authors.forename: Goran N
authors.initials: GN
authors.lastname: Kaluđerović
authors.affiliation: Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, Halle (Saale), D 06120 Halle, Germany. Electronic address: ludger.wessjohann@ipb-halle.de.
authors.forename: Ludger A
authors.initials: LA
authors.lastname: Wessjohann
authors.affiliation: Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia. Electronic address: sanjamama@ibiss.bg.ac.rs.
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatović
authors.affiliation: Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia. Electronic address: nelamax@ibiss.bg.ac.rs.
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimović-Ivanić
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D017382:Reactive Oxygen Species; D044004:Xanthones; C512910:isoxanthohumol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel
keywords: 8-Prenylnaringenin (PubChemCID: 480764); Apoptosis; Chemosensitization; Differentiation; Isoxanthohumol; Isoxanthohumol (PubChemCID: 513197); Melanoma; Paclitaxel; Paclitaxel (PubChemCID: 36314); Xanthohumol (PubChemCID: 639665)