Planta Med 2019; 85(11/12): 997-1007
DOI: 10.1055/a-0954-6704
Biological and Pharmacological Activities
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Silymarin Enriched Extract (Silybum marianum) Additive Effect on Doxorubicin-Mediated Cytotoxicity in PC-3 Prostate Cancer Cells[ 1 ]

Katerina Gioti
1  Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Kallithea, Greece
,
Anastasia Papachristodoulou
1  Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Kallithea, Greece
2  Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Zografou, Greece
,
Dimitra Benaki
2  Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Zografou, Greece
,
Sophia Havaki
3  Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
Apostolos Beloukas
4  Department of Biomedical Sciences, School of Health Sciences, University of West Attica, Greece
5  Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
,
Argyro Vontzalidou
6  Faculty of Pharmacy, Department of Pharmacognosy and Natural Products Chemistry, University of Athens, Zografou, Greece
,
Nektarios Aligiannis
6  Faculty of Pharmacy, Department of Pharmacognosy and Natural Products Chemistry, University of Athens, Zografou, Greece
,
Alexios-Leandros Skaltsounis
6  Faculty of Pharmacy, Department of Pharmacognosy and Natural Products Chemistry, University of Athens, Zografou, Greece
,
Emmanuel Mikros
2  Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Zografou, Greece
,
Roxane Tenta
1  Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Kallithea, Greece
› Author Affiliations
Further Information

Publication History

received 16 February 2019
revised 06 June 2019

accepted 10 June 2019

Publication Date:
09 July 2019 (eFirst)

Abstract

Silymarin-enriched extract (SEE) is obtained from Silybum marianum (Asteraceae). Doxorubicin (DXR) is a widely used chemotherapeutical yet with severe side effects. The goal of the present study was to assess the pharmacologic effect of SEE and its bioactive components silibinin and silychristine when administrated alone or in combination with DXR in the human prostate cancer cells (PC-3). PC-3 cells were treated with SEE, silibinin (silybins A and B), silychristine, alone, and in combination with DXR, and cell proliferation was assessed by the MTT assay. Cell cycle, apoptosis, and autophagy rate were assessed by flow cytometry. Expression levels of autophagy-related genes were quantified by qRT-PCR, ELISA and western blot while transmission electron microscopy was performed to reveal autophagic structures. Finally, NMR spectrometry was used to identify specific metabolites related to autophagy. SEE inhibited PC-3 cell proliferation in a dose-dependent manner while the co-treatment (DXR-SEE) revealed an additive cytotoxic effect. Cell cycle, apoptosis, and autophagy variations were observed in addition to altered expression levels of autophagy related genes (LC3, p62, NBR1, Beclin1, ULK1, AMBRA1), while several modifications in autophagic structures were identified after DXR-SEE co-treatment. Furthermore, treated cells showed a different metabolic profile, with significant alterations in autophagy-related metabolites such as branched-chain amino acids. In conclusion, the DXR-SEE co-treatment provokes perturbations in the autophagic mechanism of prostate cancer cells (PC-3) compared to DXR treatment alone, causing an excessive cell death. These findings propose the putative use of SEE as an adjuvant cytotoxic agent.

1 Dedicated to Professor Dr. Cosimo Pizza 70th birthday in recognition of his outstanding contribution to natural product research.