Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones.

Sergey A Dyshlovoy,Markus Graefen,Moritz Kaune,Yurii E Sabutskii,Christoph Krisp,Vladimir A Denisenko,Gunhild Von Amsberg,Valentin A Stonik,Jessica Hauschild,Ekaterina A Khmelevskaya,Hartmut Schlüter,Natalia D Pokhilo,Tobias Busenbender,Dmitry N Pelageev,Simone Venz,Ksenia L Borisova,Victor Ph Anufriev,Lyubov N Atopkina,Carsten Bokemeyer

doi:10.3390/cancers11111690

Abstract

Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC.

Highlights

Despite continuous progress in the treatment of metastatic castration-resistant prostate cancer resistance development remains a major challenge during the course of treatment with decreasing response rates and reduced progression free and overall survival with each additional treatment line [1]
In continuation of the search for new natural compounds and their synthetic derivatives capable of overcoming the resistance of drug-resistant prostate cancer, we identified several
2-methoxy-1,4-naphthoquinones to be active in human prostate cancer PC-3 cells, known to be docetaxel-resistant and hormone-independent. The cytotoxicity of these compounds was comparable in malignant PC-3 cells and in human prostate non-cancer PNT2 cells (Table S4)

Summary

Introduction

Despite continuous progress in the treatment of metastatic castration-resistant prostate cancer resistance development remains a major challenge during the course of treatment with decreasing response rates and reduced progression free and overall survival with each additional treatment line [1]. Even in aerobic conditions the cancer cells prefer glycolysis followed by lactate fermentation over more energetically efficient oxidative phosphorylation. This process which was called “aerobic glycolysis” leads to the generation of extra amounts of metabolites, which may be beneficial for the rapidly proliferating cancer cells [5]. This phenomenon known as the “Warburg effect” attracts attention as one of the promising strategies for specific tumor targeting. Glufosfamide was the first sugar-conjugated compound which has been synthesized [7], successfully passed several clinical trials [8] and is currently undergoing Phase

Results

Discussion

Conclusion