Efficacy and Mechanism of Action of Marine Alkaloid 3,10-Dibromofascaplysin in Drug-Resistant Prostate Cancer Cells

  • Mar Drugs. 2020 Dec 1;18(12):609. doi: 10.3390/md18120609.
Sergey A Dyshlovoy  1  2  3  4 ,  Moritz Kaune  1 ,  Jessica Hauschild  1 ,  Malte Kriegs  5  6 ,  Konstantin Hoffer  5  6 ,  Tobias Busenbender  1 ,  Polina A Smirnova  4 ,  Maxim E Zhidkov  4 ,  Ekaterina V Poverennaya  7 ,  Su Jung Oh-Hohenhorst  3  8 ,  Pavel V Spirin  9 ,  Vladimir S Prassolov  9 ,  Derya Tilki  3  10 ,  Carsten Bokemeyer  1 ,  Markus Graefen  3 ,  Gunhild von Amsberg  1  3
Affiliations
  • 1. Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany.
  • 2. Laboratory of Pharmacology, A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo str. 17, 690041 Vladivostok, Russian.
  • 3. Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany.
  • 4. School of Natural Sciences, Far Eastern Federal University, FEFU Campus, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russian.
  • 5. Department of Radiotherapy & Radiation Oncology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany.
  • 6. UCCH Kinomics Core Facility, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany.
  • 7. Laboratory of Proteoform Interactomics, Institute of Biomedical Chemistry, Pogodinskaya str. 10/8, 119121 Moscow, Russian.
  • 8. Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
  • 9. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, 119991 Moscow, Russian.
  • 10. Department of Urology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany.
PMID: 33271756 DOI: 10.3390/md18120609
Abstract

Efficacy and mechanism of action of marine alkaloid 3,10-dibromofascaplysin (DBF) were investigated in human prostate Cancer (PCa) cells harboring different levels of drug resistance. Anticancer activity was observed across all cell lines examined without signs of cross-resistance to Androgen Receptor targeting agents (ARTA) or taxane based chemotherapy. Kinome analysis followed by functional investigation identified JNK1/2 to be one of the molecular targets of DBF in 22Rv1 cells. In contrast, no activation of p38 and ERK1/2 MAPKs was observed. Inhibition of the drug-induced JNK1/2 activation or of the basal p38 activity resulted in increased cytotoxicity of DBF, whereas an active ERK1/2 was identified to be important for Anticancer activity of the alkaloid. Synergistic effects of DBF were observed in combination with PARP-inhibitor olaparib most likely due to the induction of ROS production by the marine alkaloid. In addition, DBF intensified effects of platinum-based drugs cisplatin and carboplatin, and taxane derivatives docetaxel and cabazitaxel. Finally, DBF inhibited AR-signaling and resensitized AR-V7-positive 22Rv1 prostate Cancer cells to enzalutamide, presumably due to AR-V7 down-regulation. These findings propose DBF to be a promising novel drug candidate for the treatment of human PCa regardless of resistance to standard therapy.

Keywords
JNK1/2; fascaplysin; natural products; prostate cancer; synergism.
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