Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of patched and increase chemotherapy efficiency on melanoma cells
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Laura Fiorini1, Marie-Aude Tribalat2, Lucy Sauvard1,2, Julie Cazareth1, Enzo Lalli1, Isabelle Broutin3, Olivier P. Thomas2,4, Isabelle Mus-Veteau1
1Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Université Nice Sophia Antipolis, CNRS, Valbonne, France
2Institut de Chimie de Nice, UMR 7272, Université Nice Sophia Antipolis, CNRS, Faculté des Sciences, Nice, France
3Laboratoire de Cristallographie et RMN Biologiques, UMR 8015, CNRS - Faculte de Pharmacie, Paris, France
4Institut Méditerranéen de Biodiversité et d’Ecologie Marine et Continentale, UMR 7263, CNRS, IRD, Université Aix-Marseille, Université Avignon, Station Marine d’Endoume, Marseille, France
Olivier P. Thomas, e-mail: [email protected]
Isabelle Mus-Veteau, e-mail: [email protected]
Keywords: Patched, chemotherapy resistance, natural sponge compounds, drug efflux antagonist, cancer
Received: March 15, 2015 Accepted: May 20, 2015 Published: June 01, 2015
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.
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