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Open AccessArticle

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

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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
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Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany
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School of Natural Sciences, Far Eastern Federal University, FEFU Campus, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russian
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Department of Radiotherapy & Radiation Oncology, Hubertus Wald Tumorzentrum–University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany
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UCCH Kinomics Core Facility, Hubertus Wald Tumorzentrum–University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany
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Laboratory of Proteoform Interactomics, Institute of Biomedical Chemistry, Pogodinskaya str. 10/8, 119121 Moscow, Russian
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Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
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Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, 119991 Moscow, Russian
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Department of Urology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany
*
Author to whom correspondence should be addressed.
Mar. Drugs 2020, 18(12), 609; https://doi.org/10.3390/md18120609
Received: 5 November 2020 / Revised: 24 November 2020 / Accepted: 27 November 2020 / Published: 1 December 2020
(This article belongs to the Collection Marine Compounds and Cancer)
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. View Full-Text
Keywords: fascaplysin; prostate cancer; JNK1/2; natural products; synergism fascaplysin; prostate cancer; JNK1/2; natural products; synergism
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MDPI and ACS Style

Dyshlovoy, S.A.; Kaune, M.; Hauschild, J.; Kriegs, M.; Hoffer, K.; Busenbender, T.; Smirnova, P.A.; Zhidkov, M.E.; Poverennaya, E.V.; Oh-Hohenhorst, S.J.; Spirin, P.V.; Prassolov, V.S.; Tilki, D.; Bokemeyer, C.; Graefen, M.; von Amsberg, G. Efficacy and Mechanism of Action of Marine Alkaloid 3,10-Dibromofascaplysin in Drug-Resistant Prostate Cancer Cells. Mar. Drugs 2020, 18, 609. https://doi.org/10.3390/md18120609

AMA Style

Dyshlovoy SA, Kaune M, Hauschild J, Kriegs M, Hoffer K, Busenbender T, Smirnova PA, Zhidkov ME, Poverennaya EV, Oh-Hohenhorst SJ, Spirin PV, Prassolov VS, Tilki D, Bokemeyer C, Graefen M, von Amsberg G. Efficacy and Mechanism of Action of Marine Alkaloid 3,10-Dibromofascaplysin in Drug-Resistant Prostate Cancer Cells. Marine Drugs. 2020; 18(12):609. https://doi.org/10.3390/md18120609

Chicago/Turabian Style

Dyshlovoy, Sergey A.; Kaune, Moritz; Hauschild, Jessica; Kriegs, Malte; Hoffer, Konstantin; Busenbender, Tobias; Smirnova, Polina A.; Zhidkov, Maxim E.; Poverennaya, Ekaterina V.; Oh-Hohenhorst, Su J.; Spirin, Pavel V.; Prassolov, Vladimir S.; Tilki, Derya; Bokemeyer, Carsten; Graefen, Markus; von Amsberg, Gunhild. 2020. "Efficacy and Mechanism of Action of Marine Alkaloid 3,10-Dibromofascaplysin in Drug-Resistant Prostate Cancer Cells" Mar. Drugs 18, no. 12: 609. https://doi.org/10.3390/md18120609

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