Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zhao, Q; Assimopoulou, AN; Klauck, SM; Damianakos, H; Chinou, I; Kretschmer, N; Rios, JL; Papageorgiou, VP; Bauer, R; Efferth, T.
Inhibition of c-MYC with involvement of ERK/JNK/MAPK and AKT pathways as a novel mechanism for shikonin and its derivatives in killing leukemia cells.
Oncotarget. 2015; 6(36):38934-38951
Doi: 10.18632/oncotarget.5380
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- Co-Autor*innen der Med Uni Graz
- Kretschmer Nadine
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- Abstract:
- Leukemia remains life-threatening despite remarkable advances in chemotherapy. The poor prognosis and drug resistance are challenging treatment. Novel drugs are urgently needed. Shikonin, a natural naphthoquinone, has been previously shown by us to be particularly effective towards various leukemia cell lines compared to solid tumors. However, the underlying mechanisms are still poorly understood. Here, we investigated shikonin and 14 derivatives on U937 leukemia cells. Four derivatives (isobutyrylshikonin, 2-methylbutyrylshikonin, isovalerylshikonin and β,β-dimethylacrylshikonin) were more active than shikonin. AnnexinV-PI analysis revealed that shikonins induced apoptosis. Cell cycle G1/S check point regulation and the transcription factor c-MYC, which plays a vital role in cell cycle regulation and proliferation, were identified as the most commonly down-regulated mechanisms upon treatment with shikonins in mRNA microarray hybridizations. Western blotting and DNA-binding assays confirmed the inhibition of c-MYC expression and transcriptional activity by shikonins. Reduction of c-MYC expression was closely associated with deregulated ERK, JNK MAPK and AKT activity, indicating their involvement in shikonin-triggered c-MYC inactivation. Molecular docking studies revealed that shikonin and its derivatives bind to the same DNA-binding domain of c-MYC as the known c-MYC inhibitors 10058-F4 and 10074-G5. This finding indicates that shikonins bind to c-MYC. The effect of shikonin on U937 cells was confirmed in other leukemia cell lines (Jurkat, Molt4, CCRF-CEM, and multidrug-resistant CEM/ADR5000), where shikonin also inhibited c-MYC expression and influenced phosphorylation of AKT, ERK1/2, and SAPK/JNK. In summary, inhibition of c-MYC and related pathways represents a novel mechanism of shikonin and its derivatives to explain their anti-leukemic activity.
- Find related publications in this database (using NLM MeSH Indexing)
- Anti-Inflammatory Agents, Non-Steroidal - pharmacology
- Cell Line, Tumor -
- Extracellular Signal-Regulated MAP Kinases - metabolism
- Humans -
- JNK Mitogen-Activated Protein Kinases - metabolism
- Leukemia - drug therapy
- Leukemia - metabolism
- Leukemia - pathology
- MAP Kinase Signaling System - drug effects
- Mitogen-Activated Protein Kinase Kinases - metabolism
- Naphthoquinones - pharmacology
- Proto-Oncogene Proteins c-akt - metabolism
- Proto-Oncogene Proteins c-myc - genetics
- Proto-Oncogene Proteins c-myc - metabolism
- Signal Transduction -
- U937 Cells -
- Find related publications in this database (Keywords)
- shikonin and its derivatives
- c-MYC
- ERK/JNK/MAP kinases
- AKT pathway
- acute leukemia