Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy

Autoren

Ean-Jeong Seo
Thomas Efferth

Autoren-URL

https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000375692900115&DestLinkType=FullRecord&DestApp=WOS_CPL

DOI

10.18632/oncotarget.7605

eISSN

1949-2553

Externe Identifier

Clarivate Analytics Document Solution ID: DL5QW
PubMed Identifier: 26921194

Ausgabe der Veröffentlichung

13

Zeitschrift

ONCOTARGET

Schlüsselwörter

translationally controlled tumor protein (TCTP)
antihistaminic compounds
levomepromazine
buclizine
cancer differentiation therapy

Paginierung

16818 - 16839

Datum der Veröffentlichung

2016

Status

Published

Titel

Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy

Sub types

Article

Ausgabe der Zeitschrift

7

Data source: Web of Science (Lite)

Autoren

Ean-Jeong Seo
Thomas Efferth

DOI

10.18632/oncotarget.7605

eISSN

1949-2553

Ausgabe der Veröffentlichung

13

Zeitschrift

Oncotarget

Sprache

en

Online publication date

2016

Paginierung

16818 - 16839

Datum der Veröffentlichung

2016

Status

Published

Herausgeber

Impact Journals, LLC

Herausgeber URL

http://dx.doi.org/10.18632/oncotarget.7605

Datum der Datenerfassung

2020

Titel

Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy

Ausgabe der Zeitschrift

7

Data source: Crossref

Abstract

Translationally controlled tumor protein (TCTP) represents an exquisite target for cancer differentiation therapy, because it was most strikingly down-regulated in tumor reversion experiments. Since TCTP is identical with the histamine releasing factor, antihistamic drugs may inhibit TCTP. Indeed, antihistaminics, such as promethazine, thioridazine, perphemazine and chlorpromazine reveal antiproliferative effects. The aim of this investigation was to study antihistaminic drugs as new TCTP inhibitors to inhibit tumor growth. Levomepromazine and buclizine showed higher in silico binding affinities to TCTP among 12 different antihistaminic compounds including the control drugs, promethazine and hydroxyzine by using Autodock4 and AutodockTools-1.5.7.rc1. Recombinant human TCTP was codon-optimized, expressed in E. coli and purified by chitin affinity chromatography. For experimental validation of in silico data, we applied microscale thermophoresis. Levomepromazine bound with a Kd of 57.2 μM (p < 0.01) and buclizine with a Kd of 433μM (p < 0.01) to recombinant TCTP. Both drugs inhibited MCF-7 breast cancer cell growth in resazurin assays. TCTP expression was down-regulated after treatment with the two drugs. Cell cycle was arrested in the G1 phase without apoptosis as confirmed by the expression of cell cycle and apoptosis-regulating proteins. Annexin V-PI staining and Trypan blue exclusion assay supported that the two drugs are cytostatic rather than cytotoxic. Induction of differentiation with two drugs was detected by the increased appearance of lipid droplets. In conclusion, levomepromazine and buclizine inhibited cancer cell growth by binding to TCTP and induction of cell differentiation. These compounds may serve as lead compounds for cancer differentiation therapy.

Addresses

Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, 55128 Mainz, Germany.

Autoren

Ean-Jeong Seo
Thomas Efferth
Thomas Efferth

DOI

10.18632/oncotarget.7605

eISSN

1949-2553

Externe Identifier

PubMed Identifier: 26921194
PubMed Central ID: PMC4941353

Open access

true

ISSN

1949-2553

Ausgabe der Veröffentlichung

13

Zeitschrift

Oncotarget

Schlüsselwörter

Humans
Histamine Antagonists
Antineoplastic Agents
Cell Differentiation
Cell Cycle Checkpoints
MCF-7 Cells
Molecular Docking Simulation
Biomarkers, Tumor
Tumor Protein, Translationally-Controlled 1

Sprache

eng

Medium

Print

Open access status

Open Access

Paginierung

16818 - 16839

Datum der Veröffentlichung

2016

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2016

Titel

Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy.

Sub types

research-article
Journal Article

Ausgabe der Zeitschrift

7

Files

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=7605&path%5B%5D=22013 https://europepmc.org/articles/PMC4941353?pdf=render

Data source: Europe PubMed Central

Abstract

Translationally controlled tumor protein (TCTP) represents an exquisite target for cancer differentiation therapy, because it was most strikingly down-regulated in tumor reversion experiments. Since TCTP is identical with the histamine releasing factor, antihistamic drugs may inhibit TCTP. Indeed, antihistaminics, such as promethazine, thioridazine, perphemazine and chlorpromazine reveal antiproliferative effects. The aim of this investigation was to study antihistaminic drugs as new TCTP inhibitors to inhibit tumor growth. Levomepromazine and buclizine showed higher in silico binding affinities to TCTP among 12 different antihistaminic compounds including the control drugs, promethazine and hydroxyzine by using Autodock4 and AutodockTools-1.5.7.rc1. Recombinant human TCTP was codon-optimized, expressed in E. coli and purified by chitin affinity chromatography. For experimental validation of in silico data, we applied microscale thermophoresis. Levomepromazine bound with a Kd of 57.2 μM (p < 0.01) and buclizine with a Kd of 433μM (p < 0.01) to recombinant TCTP. Both drugs inhibited MCF-7 breast cancer cell growth in resazurin assays. TCTP expression was down-regulated after treatment with the two drugs. Cell cycle was arrested in the G1 phase without apoptosis as confirmed by the expression of cell cycle and apoptosis-regulating proteins. Annexin V-PI staining and Trypan blue exclusion assay supported that the two drugs are cytostatic rather than cytotoxic. Induction of differentiation with two drugs was detected by the increased appearance of lipid droplets. In conclusion, levomepromazine and buclizine inhibited cancer cell growth by binding to TCTP and induction of cell differentiation. These compounds may serve as lead compounds for cancer differentiation therapy.

Date of acceptance

2016

Autoren

Ean-Jeong Seo
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/26921194

DOI

10.18632/oncotarget.7605

eISSN

1949-2553

Externe Identifier

PubMed Central ID: PMC4941353

Ausgabe der Veröffentlichung

13

Zeitschrift

Oncotarget

Schlüsselwörter

antihistaminic compounds
buclizine
cancer differentiation therapy
levomepromazine
translationally controlled tumor protein (TCTP)
Antineoplastic Agents
Biomarkers, Tumor
Cell Cycle Checkpoints
Cell Differentiation
Histamine Antagonists
Humans
MCF-7 Cells
Molecular Docking Simulation
Tumor Protein, Translationally-Controlled 1

Sprache

eng

Country

United States

Paginierung

16818 - 16839

PII

7605

Datum der Veröffentlichung

2016

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2017

Titel

Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy.

Sub types

Journal Article

Ausgabe der Zeitschrift

7

Data source: PubMed

Author's licence

CC-BY

Autoren

Ean-Jeong Seo
Thomas Efferth

Hosting institution

Universitätsbibliothek Mainz

Sammlungen

DFG-OA-Publizieren (2012 - 2017)

Resource version

Published version

DOI

10.18632/oncotarget.7605

Funding acknowledgements

DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin

File(s) embargoed

false

Open access

true

ISSN

1949-2553

Ausgabe der Veröffentlichung

13

Zeitschrift

OncoTarget

Schlüsselwörter

570 Biowissenschaften
570 Life sciences

Sprache

eng

Open access status

Open Access

Paginierung

16818 - 16839

Datum der Veröffentlichung

2016

Public URL

https://openscience.ub.uni-mainz.de/handle/20.500.12030/7915

Herausgeber

Impact Journals LLC

Herausgeber URL

http://dx.doi.org/10.18632/oncotarget.7605

Datum der Datenerfassung

2022

Datum, an dem der Datensatz öffentlich gemacht wurde

2022

Zugang

Public

Titel

Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy

Ausgabe der Zeitschrift

7

Files

interaction_of_antihistaminic-20220924203829700.pdf

Data source: OPENSCIENCE.UB