Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer
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Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer. / Dyshlovoy, Sergey A; Otte, Katharina; Alsdorf, Winfried H; Hauschild, Jessica; Lange, Tobias; Venz, Simone; Bauer, Christiane K; Bähring, Robert; Amann, Kerstin; Mandanchi, Ramin ; Schumacher, Udo; Schröder-Schwarz, Jennifer; Makarieva, Tatyana N; Guzii, Alla G; Tabakmakher, Kseniya M; Fedorov, Sergey N; Shubina, Larisa K; Kasheverov, Igor E; Ehmke, Heimo; Steuber, Thomas; Stonik, Valentin A; Bokemeyer, Carsten; Honecker, Friedemann; von Amsberg, Gunhild.
In: ONCOTARGET, Vol. 7, No. 43, 2016, p. 69703 - 69717.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer
AU - Dyshlovoy, Sergey A
AU - Otte, Katharina
AU - Alsdorf, Winfried H
AU - Hauschild, Jessica
AU - Lange, Tobias
AU - Venz, Simone
AU - Bauer, Christiane K
AU - Bähring, Robert
AU - Amann, Kerstin
AU - Mandanchi, Ramin
AU - Schumacher, Udo
AU - Schröder-Schwarz, Jennifer
AU - Makarieva, Tatyana N
AU - Guzii, Alla G
AU - Tabakmakher, Kseniya M
AU - Fedorov, Sergey N
AU - Shubina, Larisa K
AU - Kasheverov, Igor E
AU - Ehmke, Heimo
AU - Steuber, Thomas
AU - Stonik, Valentin A
AU - Bokemeyer, Carsten
AU - Honecker, Friedemann
AU - von Amsberg, Gunhild
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.18632/oncotarget.11941
DO - 10.18632/oncotarget.11941
M3 - SCORING: Journal article
C2 - 27626485
VL - 7
SP - 69703
EP - 69717
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 43
ER -
