Oncotarget

Research Papers:

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

Qiaoli Zhao _, Andreana N. Assimopoulou, Sabine M. Klauck, Harilaos Damianakos, Ioanna Chinou, Nadine Kretschmer, José-Luis Rios, Vassilios P. Papageorgiou, Rudolf Bauer and Thomas Efferth

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Oncotarget. 2015; 6:38934-38951. https://doi.org/10.18632/oncotarget.5380

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Abstract

Qiaoli Zhao1, Andreana N. Assimopoulou2, Sabine M. Klauck3, Harilaos Damianakos4, Ioanna Chinou4, Nadine Kretschmer5, José-Luis Rios6, Vassilios P. Papageorgiou2, Rudolf Bauer5, Thomas Efferth1

1Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany

2Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece

3Working Group Cancer Genome Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), Heidelberg, Germany

4Faculty of Pharmacy, University of Athens, Athens, Greece

5Department of Pharmacognosy, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria

6Department de Farmacologia, Facultat de Farmàcia, Universitat de València, Valencia, Spain

Correspondence to:

Thomas Efferth, e-mail: efferth@uni-mainz.de

Keywords: shikonin and its derivatives, c-MYC, ERK/JNK/MAP kinases, AKT pathway, acute leukemia

Received: July 09, 2015     Accepted: September 28, 2015     Published: October 09, 2015

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.


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