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

Autoren

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

Autoren-URL

https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000366114000039&DestLinkType=FullRecord&DestApp=WOS_CPL

DOI

10.18632/oncotarget.5380

eISSN

1949-2553

Externe Identifier

Clarivate Analytics Document Solution ID: CY0RS
PubMed Identifier: 26472107

Ausgabe der Veröffentlichung

36

Zeitschrift

ONCOTARGET

Schlüsselwörter

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

Paginierung

38934 - 38951

Datum der Veröffentlichung

2015

Status

Published

Titel

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

Sub types

Article

Ausgabe der Zeitschrift

6

Data source: Web of Science (Lite)

Autoren

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

DOI

10.18632/oncotarget.5380

eISSN

1949-2553

Ausgabe der Veröffentlichung

36

Zeitschrift

Oncotarget

Sprache

en

Online publication date

2015

Paginierung

38934 - 38951

Datum der Veröffentlichung

2015

Status

Published

Herausgeber

Impact Journals, LLC

Herausgeber URL

http://dx.doi.org/10.18632/oncotarget.5380

Datum der Datenerfassung

2020

Titel

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

Ausgabe der Zeitschrift

6

Data source: Crossref

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.

Addresses

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

Autoren

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

DOI

10.18632/oncotarget.5380

eISSN

1949-2553

Externe Identifier

PubMed Identifier: 26472107
PubMed Central ID: PMC4770748

Open access

true

ISSN

1949-2553

Ausgabe der Veröffentlichung

36

Zeitschrift

Oncotarget

Schlüsselwörter

Cell Line, Tumor
U937 Cells
Humans
Leukemia
Naphthoquinones
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
JNK Mitogen-Activated Protein Kinases
Proto-Oncogene Proteins c-myc
Anti-Inflammatory Agents, Non-Steroidal
Signal Transduction
MAP Kinase Signaling System
Proto-Oncogene Proteins c-akt

Sprache

eng

Medium

Print

Open access status

Open Access

Paginierung

38934 - 38951

Datum der Veröffentlichung

2015

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2015

Titel

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.

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

6

Files

https://www.oncotarget.com/article/5380/pdf/https://europepmc.org/articles/PMC4770748?pdf=render

Data source: Europe PubMed Central

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.

Date of acceptance

2015

Autoren

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

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/26472107

DOI

10.18632/oncotarget.5380

eISSN

1949-2553

Externe Identifier

PubMed Central ID: PMC4770748

Ausgabe der Veröffentlichung

36

Zeitschrift

Oncotarget

Schlüsselwörter

AKT pathway
ERK/JNK/MAP kinases
acute leukemia
c-MYC
shikonin and its derivatives
Anti-Inflammatory Agents, Non-Steroidal
Cell Line, Tumor
Extracellular Signal-Regulated MAP Kinases
Humans
JNK Mitogen-Activated Protein Kinases
Leukemia
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Naphthoquinones
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-myc
Signal Transduction
U937 Cells

Sprache

eng

Country

United States

Paginierung

38934 - 38951

PII

5380

Datum der Veröffentlichung

2015

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2016

Titel

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.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

6

Data source: PubMed

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

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