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New Guanidine Alkaloids Batzelladines O and P from the Marine Sponge Monanchora pulchra Induce Apoptosis and Autophagy in Prostate Cancer Cells

ORCID
0000-0002-7155-9245
Affiliation
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Dyshlovoy, Sergey A.;
Affiliation
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia
Shubina, Larisa K.;
Affiliation
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia
Makarieva, Tatyana N.;
Affiliation
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia
Guzii, Alla G.;
Affiliation
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Hauschild, Jessica;
Affiliation
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Strewinsky, Nadja;
Affiliation
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia
Berdyshev, Dmitrii V.;
Affiliation
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia
Kudryashova, Ekaterina K.;
Affiliation
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia
Menshov, Alexander S.;
Affiliation
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia
Popov, Roman S.;
ORCID
0000-0002-4416-7844
Affiliation
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia
Dmitrenok, Pavel S.;
Affiliation
Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Graefen, Markus;
ORCID
0000-0001-6071-7810
Affiliation
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Bokemeyer, Carsten;
Affiliation
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
von Amsberg, Gunhild

Two new guanidine alkaloids, batzelladines O ( 1 ) and P ( 2 ), were isolated from the deep-water marine sponge Monanchora pulchra. The structures of these metabolites were determined by NMR spectroscopy, mass spectrometry, and ECD. The isolated compounds exhibited cytotoxic activity in human prostate cancer cells PC3, PC3-DR, and 22Rv1 at low micromolar concentrations and inhibited colony formation and survival of the cancer cells. Batzelladines O ( 1 ) and P ( 2 ) induced apoptosis, which was detected by Western blotting as caspase-3 and PARP cleavage. Additionally, induction of pro-survival autophagy indicated as upregulation of LC3B-II and suppression of mTOR was observed in the treated cells. In line with this, the combination with autophagy inhibitor 3-methyladenine synergistically increased the cytotoxic activity of batzelladines O ( 1 ) and P ( 2 ). Both compounds were equally active in docetaxel-sensitive and docetaxel-resistant prostate cancer cells, despite exhibiting a slight p-glycoprotein substrate-like activity. In combination with docetaxel, an additive effect was observed. In conclusion, the isolated new guanidine alkaloids are promising drug candidates for the treatment of taxane-resistant prostate cancer.

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