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

Sergey A Dyshlovoy,Larisa K Shubina,Jennifer Schröder-Schwarz,Katharina Otte,Gunhild Von Amsberg,Kseniya M Tabakmakher,Sergey N Fedorov,Thomas Steuber,Igor E Kasheverov,Simone Venz,Ramin Mandanchi,Robert Bähring,Tatyana N Makarieva,Tobias Lange,Carsten Bokemeyer,Valentin A Stonik,Alla G Guzii,Friedemann Honecker,Jessica Hauschild,Christiane K Bauer,Kerstin Amann,Udo Schumacher,Heimo Ehmke,Winfried Alsdorf

doi:10.18632/oncotarget.11941

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.

Highlights

Significant progress has been made in the treatment of castration-resistant prostate cancer (CRPC) in recent years
Caspase-dependent apoptosis, inhibition of pro-survival autophagy, downregulation of Androgen receptor (AR)-V7, prostate-specific antigen (PSA) and IGF-1 expression as well as inhibition of voltage-gated potassium channels were identified as mechanisms of action
Apoptosis induction was more pronounced in 22Rv1 and VCaP cells than in PC-3 and DU145 cells which is in line with the observed IC50 values revealing strongest cytotoxic effects of Rhiz in androgen receptor splice variant 7 (AR-V7) positive cell lines (Figure 2A)

Summary

Introduction

Significant progress has been made in the treatment of castration-resistant prostate cancer (CRPC) in recent years. Trabectedin, and monomethylauristatin E (MMAE) are recently approved marine-derived anticancer drugs. Their unique mechanisms of action explains their ability to overcome resistance against other chemotherapeutic agents [6, 7] Rhizochalinin (Rhiz, referred to as aglycon of rhizochalin; Figure 1A) is a sphingolipid-like semi-synthetic compound. It is hydrolytically derived from rhizochalin [8] – a bioactive substance initially isolated from the marine sponge Rhizochalina incrustata (Figure 1A) [9]. No detailed characterization of the marine compound has been carried out to date and in vivo data are pending

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Results

Conclusion