New Marine Fungal Deoxy-14,15-Dehydroisoaustamide Resensitizes Prostate Cancer Cells to Enzalutamide
Sergey A. Dyshlovoy,
Olesya I. Zhuravleva,
Jessica Hauschild,
Tobias Busenbender,
Dmitry N. Pelageev,
Anton N. Yurchenko,
Yuliya V. Khudyakova,
Alexandr S. Antonov,
Markus Graefen,
Carsten Bokemeyer,
Gunhild von Amsberg
Affiliations
Sergey A. Dyshlovoy
Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Olesya I. Zhuravleva
Institute of High Technologies and Advanced Materials, Far Eastern Federal University, Vladivostok 690922, Russia
Jessica Hauschild
Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Tobias Busenbender
Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Dmitry N. Pelageev
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-Letiya Vladivostoka, Vladivostok 690022, Russia
Anton N. Yurchenko
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-Letiya Vladivostoka, Vladivostok 690022, Russia
Yuliya V. Khudyakova
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-Letiya Vladivostoka, Vladivostok 690022, Russia
Alexandr S. Antonov
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-Letiya Vladivostoka, Vladivostok 690022, Russia
Markus Graefen
Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
Carsten Bokemeyer
Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Gunhild von Amsberg
Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum—University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Marine fungi serve as a valuable source for new bioactive molecules bearing various biological activities. In this study, we report on the isolation of a new indole diketopiperazine alkaloid deoxy-14,15-dehydroisoaustamide (1) from the marine-derived fungus Penicillium dimorphosporum KMM 4689 associated with a soft coral. The structure of this metabolite, including its absolute configuration, was determined by HR-MS, 1D and 2D NMR as well as CD data. Compound 1 is a very first deoxyisoaustamide alkaloid possessing two double bonds in the proline ring. The isolated compound was noncytotoxic to a panel of human normal and cancer cell lines up to 100 µM. At the same time, compound 1 resensitized prostate cancer 22Rv1 cells to androgen receptor (AR) blocker enzalutamide. The mechanism of this phenomenon was identified as specific drug-induced degradation of androgen receptor transcription variant V7 (AR-V7), which also resulted in general suppression of AR signaling. Our data suggest that the isolated alkaloid is a promising candidate for combinational therapy of castration resistant prostate cancer, including drug-resistant subtypes.
