title: Marine alkaloid Monanchocidin a overcomes drug resistance by induction of autophagy and lysosomal membrane permeabilization.
abstract: Monanchocidin A (MonA) is a novel alkaloid recently isolated from the marine sponge Monanchora pulchra. The compound reveals cytotoxic activity in genitourinary cancers including cisplatin-sensitive and -resistant germ cell tumor (GCT) cell lines, hormone-sensitive and castration-resistant prostate carcinoma cell lines and different bladder carcinoma cell lines. In contrast, non-malignant cells were significantly less sensitive. MonA is highly synergistic with cisplatin in GCT cells. Induction of autophagy at lower and lysosomal membrane permeabilization (LMP) at higher concentrations were identified as the dominating modes of action. Cytotoxicity and protein degradation could be inhibited by 3-methyladenine, an inhibitor of autophagy. LMP was confirmed by loss of acridine orange staining of lysosoms and by release of cathepsin B. In conclusion, MonA exerts cytotoxic activity by mechanisms different from "classical" apoptosis, and could be a promising new compound to overcome resistance to standard therapies in genitourinary malignancies.
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Paciﬁc Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.|School of Natural Sciences, Far East Federal University, Vladivostok, Russian Federation.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Dyshlovoy
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hauschild
authors.affiliation: Nephropathology Department, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Paciﬁc Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
authors.forename: Ksenia M
authors.initials: KM
authors.lastname: Tabakmakher
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany.|Interfacultary Institute of Genetics and Functional Genomics, Department of Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Venz
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Walther
authors.affiliation: Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Paciﬁc Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
authors.forename: Alla G
authors.initials: AG
authors.lastname: Guzii
authors.affiliation: Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Paciﬁc Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Makarieva
authors.affiliation: Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Paciﬁc Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
authors.forename: Larisa K
authors.initials: LK
authors.lastname: Shubina
authors.affiliation: Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Paciﬁc Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Fedorov
authors.affiliation: Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Paciﬁc Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
authors.forename: Valentin A
authors.initials: VA
authors.lastname: Stonik
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Division of Hematology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Tumor and Breast Center ZeTuP St. Gallen, St. Gallen, Switzerland.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Honecker
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gunhild
authors.initials: G
authors.lastname: von Amsberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D019791:Guanidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects*; D013058:Mass Spectrometry; D046529:Microscopy, Electron, Transmission; D014565:Urogenital Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; C554301:monanchocidin; D019791:Guanidine
keywords: Monanchocidin A; autophagy; cisplatin resistance; germ cell tumor cells; lysosomal membrane permeabilization