Abstract 387 The anti-cancer drug sulforaphane is proteotoxic and impairs cardiac function

Introduction

Sulforaphane (SFN) is an Isothiocyanate found in cruciferous plants such as broccoli or cauliflower. It is currently tested in clinical trials as a treatment for various types of cancer such as prostate or breast cancer. The present study aimed to compare the mechanisms of action of SFN on cardiomyocyte and prostate cancer function.

Methods and Results

Chronic SFN exposure (1 µM; 7 days) of engineered heart tissue (EHT) derived from neonatal rat ventricular myocytes (NRVMs) resulted in a significant reduction in force production (mean values ± SEM: control 0.112 ± 0.005 mN, n=53; DMSO 0.123±0.009 mN, n=29; SFN 0.094±0.007, n= 27), impairment of the Frank Starling response to stretch activation (mean values ± SEM: control 337 ± 38μm, n=7; DMSO 353±25μm, n=8; SFN 191±16μm, n=7), increased lactate accumulation and a significant reduction in mitochondrial membrane potential.

Chronic exposure of human PC3 prostate cancer cells to SFN (0.1 -30 µM; 7 days) resulted in a significant reduction in cell proliferation (IC50 of 4,1±0.087 μM, n=6) as demonstrated in an trypan blue proliferation assay. Analysis of the medium composition revealed a higher ratio of produced lactate to the consumed glucose in SFN treated cells.

Western immunoblot analysis showed an increased ratio of the microtubule-associated protein 1A/1B-light chain 3 -phosphatidylethanolamine conjugate (LC3-II) to the cytosolic LC3 (LC3-I) and an increase in cleaved caspase 3 after exposure to SFN in both, NRVMs and PC3 cells.

Conclusion

The results obtained in NRVMs and prostate cancer cells suggest that SFN exerts proteotoxic effects by modulating autophagy. This might contribute to the therapeutically desired anti-cancer effect of SFN, but highlights its potential to mediate cardiovascular side effects in patients.

Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9
The anti-cancer drug sulforaphane is proteotoxic and impairs cardiac function
J. In den Birken¹, L. Rathjens¹, S. Dyshlovoy², T. Rohlfing², T. Brand³, E. Orthey¹, S. R. Singh¹, S. Schlossarek¹, G. von Amsberg¹, K. Stathopoulou⁴, K. Lorenz³, L. Carrier⁴, A. Rhoden¹, F. Cuello⁵
¹Universitätsklinikum Hamburg-Eppendorf, Hamburg; ²Medizinische Klinik und Poliklinik, Universitätsklinik Hamburg-Eppendorf, Hamburg; ³Institut für Pharmakologie und Toxikologie, Universitätsklinikum Würzburg, Würzburg; ⁴Institut für Klinische Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg; ⁵Institut für Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg;
Introduction Sulforaphane (SFN) is an Isothiocyanate found in cruciferous plants such as broccoli or cauliflower. It is currently tested in clinical trials as a treatment for various types of cancer such as prostate or breast cancer. The present study aimed to compare the mechanisms of action of SFN on cardiomyocyte and prostate cancer function. Methods and Results Chronic SFN exposure (1 µM; 7 days) of engineered heart tissue (EHT) derived from neonatal rat ventricular myocytes (NRVMs) resulted in a significant reduction in force production (mean values ± SEM: control 0.112 ± 0.005 mN, n=53; DMSO 0.123±0.009 mN, n=29; SFN 0.094±0.007, n= 27), impairment of the Frank Starling response to stretch activation (mean values ± SEM: control 337 ± 38μm, n=7; DMSO 353±25μm, n=8; SFN 191±16μm, n=7), increased lactate accumulation and a significant reduction in mitochondrial membrane potential. Chronic exposure of human PC3 prostate cancer cells to SFN (0.1 -30 µM; 7 days) resulted in a significant reduction in cell proliferation (IC50 of 4,1±0.087 μM, n=6) as demonstrated in an trypan blue proliferation assay. Analysis of the medium composition revealed a higher ratio of produced lactate to the consumed glucose in SFN treated cells. Western immunoblot analysis showed an increased ratio of the microtubule-associated protein 1A/1B-light chain 3 -phosphatidylethanolamine conjugate (LC3-II) to the cytosolic LC3 (LC3-I) and an increase in cleaved caspase 3 after exposure to SFN in both, NRVMs and PC3 cells. Conclusion The results obtained in NRVMs and prostate cancer cells suggest that SFN exerts proteotoxic effects by modulating autophagy. This might contribute to the therapeutically desired anti-cancer effect of SFN, but highlights its potential to mediate cardiovascular side effects in patients.
https://dgk.org/kongress_programme/ht2021/BS902.htm