New Guanidine Alkaloids Batzelladines O and P from the Marine Sponge <i>Monanchora pulchra</i> Induce Apoptosis and Autophagy in Prostate Cancer Cells
Sergey A. Dyshlovoy,
Larisa K. Shubina,
Tatyana N. Makarieva,
Alla G. Guzii,
Jessica Hauschild,
Nadja Strewinsky,
Dmitrii V. Berdyshev,
Ekaterina K. Kudryashova,
Alexander S. Menshov,
Roman S. Popov,
Pavel S. Dmitrenok,
Markus Graefen,
Carsten Bokemeyer,
Gunhild von Amsberg
Affiliations
Sergey A. Dyshlovoy
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
Larisa K. Shubina
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
Tatyana N. Makarieva
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
Alla G. Guzii
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
Jessica Hauschild
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
Nadja Strewinsky
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
Dmitrii V. Berdyshev
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
Ekaterina K. Kudryashova
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
Alexander S. Menshov
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
Roman S. Popov
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
Pavel S. Dmitrenok
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
Markus Graefen
Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Carsten Bokemeyer
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
Gunhild von Amsberg
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
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.
