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Molecules 2018, 23(11), 2823; https://doi.org/10.3390/molecules23112823

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

1
Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitaetsplatz 4/1, 8010 Graz, Austria
2
Department of Hematology, Internal Medicine, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria
3
Department for Biomedical Research, Medical University Graz, Roseggerweg 48, 8036 Graz, Austria
4
Institute for Diabetes and Cancer (IDC), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
5
Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, 69120 Heidelberg, Germany
6
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
7
Department of Orthopedics and Trauma, Medical University of Graz, Auenbruggerplatz 5, 8036 Graz, Austria
*
Author to whom correspondence should be addressed.
Received: 4 October 2018 / Revised: 19 October 2018 / Accepted: 22 October 2018 / Published: 30 October 2018
(This article belongs to the Special Issue Natural Product Isolation, Identification and Biological Activity)
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Abstract

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. View Full-Text
Keywords: β-β-dimethylacrylshikonin; melanoma; p62; autophagy; ROS generation; mitochondrial membrane potential β-β-dimethylacrylshikonin; melanoma; p62; autophagy; ROS generation; mitochondrial membrane potential
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kretschmer, N.; Deutsch, A.; Durchschein, C.; Rinner, B.; Stallinger, A.; Higareda-Almaraz, J.C.; Scheideler, M.; Lohberger, B.; Bauer, R. 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. Molecules 2018, 23, 2823.

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