title: The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer.
abstract: Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC), outcome of patients remains poor due to the development of drug resistance. Thus, new drugs are urgently needed. We investigated efficacy, toxicity and mechanism of action of marine triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. FrA revealed high efficacy in human prostate cancer cells, while non-malignant cells were less sensitive. Remarkably, proliferation and colony formation of cells resistant to enzalutamide and abiraterone (due to the androgen receptor splice variant AR-V7) were also significantly inhibited by FrA. The marine compound caused cell type specific cell cycle arrest and induction of caspase-dependent or -independent apoptosis. Up-regulation or induction of several pro-apoptotic proteins (Bax, Bad, PTEN), cleavage of PARP and caspase-3 and down-regulation of anti-apoptotic proteins (survivin and Bcl-2) were detected in treated cells. Global proteome analysis revealed regulation of proteins involved in formation of metastases, tumor cell invasion, and apoptosis, like keratin 81, CrkII, IL-1β and cathepsin B. Inhibition of pro-survival autophagy was observed following FrA exposure. In vivo, FrA inhibited tumor growth of PC-3 and DU145 cells with a notable reduction of lung metastasis, as well as circulating tumor cells in the peripheral blood. Increased lymphocyte counts of treated animals might indicate an immune modulating effect of FrA. In conclusion, our results suggest that FrA is a promising new drug for the treatment of mCRPC. Induction of apoptosis, inhibition of pro-survival autophagy, and immune modulatory effects are suspected modes of actions.
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.|Laboratory of bioactive compounds, Department of bioorganic chemistry and biotechnology, School of Natural Sciences, Far Eastern 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.|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: Ekaterina S
authors.initials: ES
authors.lastname: Menchinskaya
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany.|Department of Functional Genomics, Interfacultary Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Venz
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: Stefanie
authors.initials: S
authors.lastname: Rast
authors.affiliation: Nephropathology Department, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
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: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Otte
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: Vladimir I
authors.initials: VI
authors.lastname: Kalinin
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: Alexandra S
authors.initials: AS
authors.lastname: Silchenko
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 A
authors.initials: SA
authors.lastname: Avilov
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: Winfried
authors.initials: W
authors.lastname: Alsdorf
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: Ramin
authors.initials: R
authors.lastname: Madanchi
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: Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
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: Dmitry L
authors.initials: DL
authors.lastname: Aminin
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: 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: 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.|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: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006027:Glycosides / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015203:Reproducibility of Results; D014315:Triterpenes / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D006027:Glycosides; D014315:Triterpenes; C534797:frondoside A
keywords: anti-metastatic activity; apoptosis; autophagy; castration-resistant prostate cancer; frondoside A