Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer
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Sergey A. Dyshlovoy1,2,3,*, Katharina Otte1,*, Winfried H. Alsdorf1, Jessica Hauschild1, Tobias Lange4, Simone Venz5, Christiane K. Bauer6, Robert Bähring6, Kerstin Amann7, Ramin Mandanchi1, Udo Schumacher4, Jennifer Schröder-Schwarz4, Tatyana N. Makarieva2, Alla G. Guzii2, Kseniya M. Tabakmakher2, Sergey N. Fedorov2, Larisa K. Shubina2, Igor E. Kasheverov8, Heimo Ehmke6, Thomas Steuber9, Valentin A. Stonik2, Carsten Bokemeyer1, Friedemann Honecker1,10, Gunhild von Amsberg1
1University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany
2G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation
3School of Natural Sciences, Far Eastern Federal University, Vladivostok, Russian Federation
4Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany
6University Medical Center Hamburg-Eppendorf, Department of Cellular and Integrative Physiology, Hamburg, Germany
7Nephropathology Department, University Medical Center Erlangen, Erlangen, Germany
8Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
9University Medical Center Hamburg-Eppendorf Martiniklinik, Prostate Cancer Center, Hamburg, Germany
10Tumor and Breast Center ZeTuP St. Gallen, St. Gallen, Switzerland
*These authors contributed equally to this work
Sergey A. Dyshlovoy, email: [email protected]
Keywords: rhizochalinin, castration resistant prostate cancer, AR-V7, apoptosis, autophagy
Received: April 27, 2016 Accepted: September 02, 2016 Published: September 10, 2016
Development of drug resistance is an inevitable phenomenon in castration-resistant prostate cancer (CRPC) cells requiring novel therapeutic approaches. In this study, efficacy and toxicity of Rhizochalinin (Rhiz) – a novel sphingolipid-like marine compound – was evaluated in prostate cancer models, resistant to currently approved standard therapies. In vitro activity and mechanism of action of Rhiz were examined in the human prostate cancer cell lines PC-3, DU145, LNCaP, 22Rv1, and VCaP. Rhiz significantly reduced cell viability at low micromolar concentrations showing most pronounced effects in enzalutamide and abiraterone resistant AR-V7 positive cells. Caspase-dependent apoptosis, inhibition of pro-survival autophagy, downregulation of AR-V7, PSA and IGF-1 expression as well as inhibition of voltage-gated potassium channels were identified as mechanisms of action. Remarkably, Rhiz re-sensitized AR-V7 positive cells to enzalutamide and increased efficacy of taxanes.
In vivo activity and toxicity were evaluated in PC-3 and 22Rv1 NOD SCID mouse xenograft models using i.p. administration. Rhiz significantly reduced growth of PC-3 and 22Rv1 tumor xenografts by 27.0% (p = 0.0156) and 46.8% (p = 0.047) compared with controls with an increased fraction of tumor cells showing apoptosis secondary to Rhiz exposure. In line with the in vitro data, Rhiz was most active in AR-V7 positive xenografts in vivo. In animals, no severe side effects were observed.
In conclusion, Rhiz is a promising novel marine-derived compound characterized by a unique combination of anticancer properties. Its further clinical development is of high impact for patients suffering from drug resistant prostate cancer especially those harboring AR-V7 mediated resistance to enzalutamide and abiraterone.
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