title: Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells.
abstract: Multidrug resistance has appeared to mitigate the efficiency of anticancer drugs and the possibility of successful cancer chemotherapy. The Hedgehog receptor Patched is a multidrug transporter expressed in several cancers and as such it represents a new target to circumvent chemotherapy resistance. We report herein that paniceins and especially panicein A hydroquinone, natural meroterpenoids produced by the Mediterranean sponge Haliclona (Soestella) mucosa, inhibit the doxorubicin efflux activity of Patched and enhance the cytotoxicity of this chemotherapeutic agent on melanoma cells in vitro. These results are supported by the molecular docking performed on the structure of the bacterial drug efflux pump AcrB and on the Patched model built from AcrB structure. Docking calculations show that panicein A hydroquinone interacts with AcrB and Patched model close to the doxorubicin binding site. This compound thus appears as the first antagonist of the doxorubicin efflux activity of Patched. The use of inhibitors of Patched drug efflux activity in combination with classical chemotherapy could represent a novel approach to reduce tumor drug resistance, recurrence and metastasis.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Université Nice Sophia Antipolis, CNRS, Valbonne, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Fiorini
authors.affiliation: Institut de Chimie de Nice, UMR 7272, Université Nice Sophia Antipolis, CNRS, Faculté des Sciences, Nice, France.
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Tribalat
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Université Nice Sophia Antipolis, CNRS, Valbonne, France.|Institut de Chimie de Nice, UMR 7272, Université Nice Sophia Antipolis, CNRS, Faculté des Sciences, Nice, France.
authors.forename: Lucy
authors.initials: L
authors.lastname: Sauvard
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Université Nice Sophia Antipolis, CNRS, Valbonne, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Cazareth
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Université Nice Sophia Antipolis, CNRS, Valbonne, France.
authors.forename: Enzo
authors.initials: E
authors.lastname: Lalli
authors.affiliation: Laboratoire de Cristallographie et RMN Biologiques, UMR 8015, CNRS - Faculte de Pharmacie, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Broutin
authors.affiliation: Institut de Chimie de Nice, UMR 7272, Université Nice Sophia Antipolis, CNRS, Faculté des Sciences, Nice, France.|Institut Méditerranéen de Biodiversité et d'Ecologie Marine et Continentale, UMR 7263, CNRS, IRD, Université Aix-Marseille, Université Avignon, Station Marine d'Endoume, Marseille, France.
authors.forename: Olivier P
authors.initials: OP
authors.lastname: Thomas
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Université Nice Sophia Antipolis, CNRS, Valbonne, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mus-Veteau
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D000072079:Patched Receptors; D011161:Porifera / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C501273:panicein A; D004317:Doxorubicin
keywords: Patched; cancer; chemotherapy resistance; drug efflux antagonist; natural sponge compounds