New Marine Fungal Deoxy-14,15-Dehydroisoaustamide Resensitizes Prostate Cancer Cells to Enzalutamide

  • Mar Drugs. 2023 Jan 14;21(1):54. doi: 10.3390/md21010054.
Sergey A Dyshlovoy  1  2 ,  Olesya I Zhuravleva  2  3 ,  Jessica Hauschild  1 ,  Tobias Busenbender  1 ,  Dmitry N Pelageev  3 ,  Anton N Yurchenko  3 ,  Yuliya V Khudyakova  3 ,  Alexandr S Antonov  3 ,  Markus Graefen  4 ,  Carsten Bokemeyer  1 ,  Gunhild von Amsberg  1  4
Affiliations
  • 1. 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.
  • 2. Institute of High Technologies and Advanced Materials, Far Eastern Federal University, Vladivostok 690922, Russia.
  • 3. G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-Letiya Vladivostoka, Vladivostok 690022, Russia.
  • 4. Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
PMID: 36662227 DOI: 10.3390/md21010054
Abstract

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.

Keywords
Penicillium dimorphosporum; androgen receptor; enzalutamide; prenylated indole alkaloid; prostate cancer; secondary metabolites.
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