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Background: Chordoma, slow growing bone tumours originating from remnants of the notochord, leave affected patients with a median survival of six years. The high recurrence rate of chordoma, together with limited treatment options and bad overall prognosis, make the development of new treatment options urgently necessary.
Purpose: In this study, the potential of two natural products, silibinin and β-β-dimethylacrylshikonin (DMAS), was tested on clival (MUG-CC1 and UM-Chor1) as well as sacral (MUG-Chor1 and U-CH2) chordoma cell lines. The treatment was administered both as single- and combined therapy.
Methods: For investigation of cell viability, the Cell Titer 96 Aqueous Non-Radioactive Cell Proliferation Assay Kit was used. Apoptosis induction was studied by flow cytometry, (Annexin V/SYTOX Green, caspase-3) and RT-qPCR. Pathway analyses were performed by western blot.
Results: Both drugs were found to reduce cell viability alone as well as in combination in a dose dependent manner, with DMAS being more efficient than silibinin. The mode of cell death was mainly apoptosis in DMAS treated samples, while the combination therapy led to apoptosis as well as late-apoptosis/necrosis. Silibinin therapy alone, although reducing cell viability, did not lead to significant apoptotic effects in the performed assays. Focussing on the molecular mechanism of DMAS induced apoptosis, it was found that major genes of the mitochondrial apoptosis pathway, like NOXA and PUMA were overexpressed. Additionally, western blot experiments showed a decrease of ERK/pERK, STAT3/pSTAT3 (Tyr705) and AKT/pAKT expression/activation levels under DMAS treatment.
Conclusion: DMAS is a promising new candidate for chordoma therapy, while silibinin or a combination of both is less favourable.
Apoptosis; Chordoma; Silibinin; β-β-dimethylacrylshikonin.
Influence of Silibinin and β-β-Dimethylacrylshikonin on Chordoma Cells
Zohreh Jahanafrooz 1, Alexander Stallinger 2, Ines Anders 2, Florian Kleinegger 3, Birgit Lohberger 4, Christin Durchschein 5, Rudolf Bauer 5, Alexander Deutsch 6, Beate Rinner 7, Nadine Kretschmer 5
2018 Oct 1
β,β-Dimethylacrylshikonin (DMAS) is an anti-cancer compound extracted from the roots of Lithospermum erythrorhizon. The present study aims to investigate the effects of DMAS on human lung adenocarcinoma cells in vitro and explore the mechanisms of its anti-cancer action. We showed that DMAS markedly inhibited cell viability in a dose- and time-dependent way, and induced apoptosis as well as autophagy in human lung adenocarcinoma cells. Furthermore, we found that DMAS stimulated endoplasmic reticulum stress and mediated autophagy through the PERK-eIF2α-ATF4-CHOP and IRE1-TRAF2-JNK axes of the unfolded protein response in human lung adenocarcinoma cells. We also showed that the autophagy induced by DMAS played a prosurvival role in human lung adenocarcinoma cells and attenuated the apoptotic cascade. Collectively, combined treatment of DMAS and pharmacological autophagy inhibitors could offer an effective therapeutic strategy for lung adenocarcinoma treatment.
apoptosis; autophagy; endoplasmic reticulum stress; lung adenocarcinoma; β,β-dimethylacrylshikonin.
Endoplasmic Reticulum Stress-Mediated Autophagy Protects Against β,β-Dimethylacrylshikonin-Induced Apoptosis in Lung Adenocarcinoma Cells
Haibing Wang 1, Gaochenxi Zhang 2
Skin cancer is currently diagnosed as one in every three cancers. Melanoma, the most aggressive form of skin cancer, is responsible for 79% of skin cancer deaths and the incidence is rising faster than in any other solid tumor type. Previously, we have demonstrated that dimethylacrylshikonin (DMAS), isolated from the roots of Onosma paniculata (Boraginaceae), exhibited the lowest IC50 values against different tumor types out of several isolated shikonin derivatives. DMAS was especially cytotoxic towards melanoma cells and led to apoptosis and cell cycle arrest. In this study, we performed a comprehensive gene expression study to investigate the mechanism of action in more detail. Gene expression signature was compared to vehicle-treated WM164 control cells after 24 h of DMAS treatment; where 1192 distinct mRNAs could be identified as expressed in all replicates and 89 were at least 2-fold differentially expressed. DMAS favored catabolic processes and led in particular to p62 increase which is involved in cell growth, survival, and autophagy. More in-depth experiments revealed that DMAS led to autophagy, ROS generation, and loss of mitochondrial membrane potential in different melanoma cells. It has been reported that the induction of an autophagic cell death represents a highly effective approach in melanoma therapy.
ROS generation; autophagy; melanoma; mitochondrial membrane potential; p62; β-β-dimethylacrylshikonin.
Comparative Gene Expression Analysis in WM164 Melanoma Cells Revealed That β- β-Dimethylacrylshikonin Leads to ROS Generation, Loss of Mitochondrial Membrane Potential, and Autophagy Induction
Nadine Kretschmer 1, Alexander Deutsch 2, Christin Durchschein 3, Beate Rinner 4, Alexander Stallinger 5, Juan Carlos Higareda-Almaraz 6 7 8, Marcel Scheideler 9 10 11, Birgit Lohberger 12, Rudolf Bauer 13
2018 Oct 30