Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer.

Abstract

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.

• Authors: Sergey A Dyshlovoy, Katharina Otte, Winfried H Alsdorf, Jessica Hauschild, Tobias Lange, Simone Venz, Christiane K Bauer, Robert Bähring, Kerstin Amann, Ramin Mandanchi, Udo Schumacher, Jennifer Schröder-Schwarz, Tatyana N Makarieva, Alla G Guzii, Kseniya M Tabakmakher, Sergey N Fedorov, Larisa K Shubina, Igor E Kasheverov, Heimo Ehmke, Thomas Steuber, Valentin A Stonik, Carsten Bokemeyer, Friedemann Honecker, Gunhild von Amsberg
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 43 Pg. 69703-69717 (Oct 25 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27626485 (Publication Type: Journal Article)

Chemical References

• Fatty Alcohols
• Potassium Channel Blockers
• Taxoids
• rhizochalinin
• Docetaxel
• Insulin-Like Growth Factor I
• Prostate-Specific Antigen
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Caspases (physiology)
• Cell Line, Tumor
• Docetaxel
• Fatty Alcohols (adverse effects, pharmacology, therapeutic use)
• Humans
• Insulin-Like Growth Factor I (analysis)
• Male
• Mice
• Potassium Channel Blockers (pharmacology)
• Prostate-Specific Antigen (analysis)
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Taxoids (pharmacology)