Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer.
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.
University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany.|G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation.|School of Natural Sciences, Far Eastern Federal University, Vladivostok, Russian Federation.
Sergey A
SA
Dyshlovoy
University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany.
Katharina
K
Otte
University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany.
Winfried H
WH
Alsdorf
University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany.
Jessica
J
Hauschild
Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Tobias
T
Lange
Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany.
Simone
S
Venz
University Medical Center Hamburg-Eppendorf, Department of Cellular and Integrative Physiology, Hamburg, Germany.
Christiane K
CK
Bauer
University Medical Center Hamburg-Eppendorf, Department of Cellular and Integrative Physiology, Hamburg, Germany.
Robert
R
Bähring
Nephropathology Department, University Medical Center Erlangen, Erlangen, Germany.
Kerstin
K
Amann
University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany.
Ramin
R
Mandanchi
Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Udo
U
Schumacher
Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Jennifer
J
Schröder-Schwarz
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation.
Tatyana N
TN
Makarieva
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation.
Alla G
AG
Guzii
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation.
Kseniya M
KM
Tabakmakher
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation.
Sergey N
SN
Fedorov
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation.
Larisa K
LK
Shubina
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
Igor E
IE
Kasheverov
University Medical Center Hamburg-Eppendorf, Department of Cellular and Integrative Physiology, Hamburg, Germany.
Heimo
H
Ehmke
University Medical Center Hamburg-Eppendorf Martiniklinik, Prostate Cancer Center, Hamburg, Germany.
Thomas
T
Steuber
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation.
Valentin A
VA
Stonik
University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany.
Carsten
C
Bokemeyer
University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany.|Tumor and Breast Center ZeTuP St. Gallen, St. Gallen, Switzerland.
Friedemann
F
Honecker
University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany.
Gunhild
G
von Amsberg
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005233:Fatty Alcohols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D051379:Mice; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000032:analysis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D043823:Taxoids / Q000494:pharmacology
D005233:Fatty Alcohols; D026902:Potassium Channel Blockers; D043823:Taxoids; C000625958:rhizochalinin; D000077143:Docetaxel; D007334:Insulin-Like Growth Factor I; D017430:Prostate-Specific Antigen; D020169:Caspases
AR-V7; apoptosis; autophagy; castration resistant prostate cancer; rhizochalinin