Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zhao, Q; Kretschmer, N; Bauer, R; Efferth, T.
Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib.
Int J Cancer. 2015; 137(6):1446-1456
Doi: 10.1002/ijc.29483
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- Co-Autor*innen der Med Uni Graz
- Kretschmer Nadine
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- Abstract:
- Overexpression and mutation of the epidermal growth factor receptor (EGFR) gene play a causal role in tumorigenesis and resistance to treatment of glioblastoma (GBM). EGFR inhibitors such as erlotinib are currently used for the treatment of GBM; however, their efficacy has been limited due to drug resistance. New treatment strategies are therefore urgently needed. Shikonin, a natural naphthoquinone, induces both apoptosis and necroptosis in human glioma cells, but the effectiveness of erlotinib-shikonin combination treatment as well as the underlying molecular mechanisms is unknown yet. In this study, we investigated erlotinib in combination with shikonin and 14 shikonin derivatives in parental U87MG and transfected U87MG.ΔEGFR GBM cells. Most of the shikonin derivatives revealed strong cytotoxicity. Shikonin together with five other derivatives, namely deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkannin showed synergistic cytotoxicity toward U87MG.ΔEGFR in combination with erlotinib. Moreover, the combined cytotoxic effect of shikonin and erlotinib was further confirmed with another three EGFR-expressing cell lines, BS153, A431 and DK-MG. Shikonin not only dose-dependently inhibited EGFR phosphorylation and decreased phosphorylation of EGFR downstream molecules, including AKT, P44/42MAPK and PLCγ1, but also together with erlotinib synergistically inhibited ΔEGFR phosphorylation in U87MG.ΔEGFR cells as determined by Loewe additivity and Bliss independence drug interaction models. These results suggest that the combination of erlotinib with shikonin or its derivatives might be a potential strategy to overcome drug resistance to erlotinib. © 2015 UICC.
- Find related publications in this database (using NLM MeSH Indexing)
- Anthraquinones - administration & dosage
- Antineoplastic Combined Chemotherapy Protocols - therapeutic use
- Cell Line, Tumor -
- Drug Synergism -
- ErbB Receptors - antagonists & inhibitors
- Erlotinib Hydrochloride -
- Glioblastoma - drug therapy
- Glioblastoma - metabolism
- Humans -
- Mitogen-Activated Protein Kinases - metabolism
- Naphthoquinones - administration & dosage
- Phosphorylation - drug effects
- Proto-Oncogene Proteins c-akt - metabolism
- Quinazolines - administration & dosage
- Signal Transduction - drug effects
- Find related publications in this database (Keywords)
- shikonin
- naphthoquinone
- epidermal growth factor receptor
- drug resistance
- synergism
- tyrosine kinase inhibitor