Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking

Autoren

Mohamed Saeed
Onat Kadioglu
Hassan Khalid
Yoshikazu Sugimoto
Thomas Efferth

DOI

10.1016/j.jnutbio.2014.09.008

ISSN

0955-2863

Ausgabe der Veröffentlichung

1

Zeitschrift

The Journal of Nutritional Biochemistry

Sprache

en

Paginierung

44 - 56

Datum der Veröffentlichung

2015

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.jnutbio.2014.09.008

Datum der Datenerfassung

2023

Titel

Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking

Ausgabe der Zeitschrift

26

Data source: Crossref

Abstract

Apigenin is a common dietary flavonoid with considerable cytotoxic activity in vitro and in vivo. Despite many mechanistic studies, less is known about resistance factors hampering apigenin's activity. We investigated the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5. Multidrug-resistant cells overexpressing these ABC transporters were not cross-resistant toward apigenin. Moreover, apigenin inhibited not only P-glycoprotein but also BCRP by increasing cellular uptake of doxorubicin and synergistic inhibition of cell viability in combination with doxorubicin or docetaxel in multidrug-resistant cells. To perform in silico molecular docking studies, we first generated homology models for human P-glycoprotein and ABCB5 based on the crystal structure of murine P-glycoprotein. Their nucleotide binding domains (NDBs) revealed the highest degrees of sequence homologies (89%-100%), indicating that ATP binding and cleavage is of crucial importance for ABC transporters. Molecular docking of apigenin bound to the NDBs of P-glycoprotein and ABCB5 in molecular docking studies. Hence, apigenin may compete with ATP for NDB-binding leading to energy depletion to fuel the transport of ABC transporter substrates. Furthermore, we performed COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression profiles of the National Cancer Institute tumor cell line panel. Microarray-based mRNA expressions of genes of diverse biological functions (signal transduction, transcriptional regulation, ubiquitination, autophagy, metabolic activity, xenobiotic detoxification and microtubule formation) significantly predicted responsiveness of tumor cells to apigenin. In conclusion, apigenin's activity is not hampered by classical mechanisms of multidrug resistance and the inhibition of ABC transporters by apigenin indicates that apigenin may overcome multidrug resistance in otherwise refractory tumors.

Addresses

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

Autoren

Mohamed Saeed
Onat Kadioglu
Hassan Khalid
Yoshikazu Sugimoto
Thomas Efferth
Thomas Efferth

DOI

10.1016/j.jnutbio.2014.09.008

eISSN

1873-4847

Externe Identifier

PubMed Identifier: 25459885

Open access

false

ISSN

0955-2863

Ausgabe der Veröffentlichung

1

Zeitschrift

The Journal of nutritional biochemistry

Schlüsselwörter

Cell Line, Tumor
Animals
Humans
Mice
Apigenin
Doxorubicin
ATP-Binding Cassette Transporters
Neoplasm Proteins
RNA, Messenger
Cluster Analysis
Inhibitory Concentration 50
Computational Biology
Pharmacogenetics
Drug Resistance, Multiple
Protein Conformation
Drug Resistance, Neoplasm
HEK293 Cells
Polyphenols
Molecular Docking Simulation
ATP Binding Cassette Transporter, Subfamily B, Member 1

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

44 - 56

Datum der Veröffentlichung

2015

Status

Published

Datum der Datenerfassung

2014

Titel

Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking.

Sub types

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

Ausgabe der Zeitschrift

26

Data source: Europe PubMed Central

Abstract

Apigenin is a common dietary flavonoid with considerable cytotoxic activity in vitro and in vivo. Despite many mechanistic studies, less is known about resistance factors hampering apigenin's activity. We investigated the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5. Multidrug-resistant cells overexpressing these ABC transporters were not cross-resistant toward apigenin. Moreover, apigenin inhibited not only P-glycoprotein but also BCRP by increasing cellular uptake of doxorubicin and synergistic inhibition of cell viability in combination with doxorubicin or docetaxel in multidrug-resistant cells. To perform in silico molecular docking studies, we first generated homology models for human P-glycoprotein and ABCB5 based on the crystal structure of murine P-glycoprotein. Their nucleotide binding domains (NDBs) revealed the highest degrees of sequence homologies (89%-100%), indicating that ATP binding and cleavage is of crucial importance for ABC transporters. Molecular docking of apigenin bound to the NDBs of P-glycoprotein and ABCB5 in molecular docking studies. Hence, apigenin may compete with ATP for NDB-binding leading to energy depletion to fuel the transport of ABC transporter substrates. Furthermore, we performed COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression profiles of the National Cancer Institute tumor cell line panel. Microarray-based mRNA expressions of genes of diverse biological functions (signal transduction, transcriptional regulation, ubiquitination, autophagy, metabolic activity, xenobiotic detoxification and microtubule formation) significantly predicted responsiveness of tumor cells to apigenin. In conclusion, apigenin's activity is not hampered by classical mechanisms of multidrug resistance and the inhibition of ABC transporters by apigenin indicates that apigenin may overcome multidrug resistance in otherwise refractory tumors.

Date of acceptance

2014

Autoren

Mohamed Saeed
Onat Kadioglu
Hassan Khalid
Yoshikazu Sugimoto
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/25459885

DOI

10.1016/j.jnutbio.2014.09.008

eISSN

1873-4847

Ausgabe der Veröffentlichung

1

Zeitschrift

J Nutr Biochem

Schlüsselwörter

Chemotherapy
Flavonoids
Multidrug resistance
Natural products, Pharmacogenomics, Molecular docking and modelling.
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP-Binding Cassette Transporters
Animals
Apigenin
Cell Line, Tumor
Cluster Analysis
Computational Biology
Doxorubicin
Drug Resistance, Multiple
Drug Resistance, Neoplasm
HEK293 Cells
Humans
Inhibitory Concentration 50
Mice
Molecular Docking Simulation
Neoplasm Proteins
Pharmacogenetics
Polyphenols
Protein Conformation
RNA, Messenger

Sprache

eng

Country

United States

Paginierung

44 - 56

PII

S0955-2863(14)00206-X

Datum der Veröffentlichung

2015

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking.

Sub types

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

Ausgabe der Zeitschrift

26

Data source: PubMed

Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking

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