Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking

Autoren

Mohamed Saeed
Victor Kuete
Onat Kadioglu
Jonas Börtzler
Hassan Khalid
Henry Johannes Greten
Thomas Efferth

DOI

10.1016/j.phymed.2014.07.011

ISSN

0944-7113

Ausgabe der Veröffentlichung

12

Zeitschrift

Phytomedicine

Sprache

en

Paginierung

1525 - 1533

Datum der Veröffentlichung

2014

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.phymed.2014.07.011

Datum der Datenerfassung

2019

Titel

Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking

Ausgabe der Zeitschrift

21

Data source: Crossref

Abstract

A main problem in oncology is the development of drug-resistance. Some plant-derived lignans are established in cancer therapy, e.g. the semisynthetic epipodophyllotoxins etoposide and teniposide. Their activity is, unfortunately, hampered by the ATP-binding cassette (ABC) efflux transporter, P-glycoprotein. Here, we investigated the bisphenolic honokiol derived from Magnolia officinalis. P-glycoprotein-overexpressing CEM/ADR5000 cells were not cross-resistant to honokiol, but MDA-MB-231 BRCP cells transfected with another ABC-transporter, BCRP, revealed 3-fold resistance. Further drug resistance mechanisms analyzed study was the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). HCT116 p53(-/-) did not reveal resistance to honokiol, and EGFR-transfected U87.MG EGFR cells were collateral sensitive compared to wild-type cells (degree of resistance: 0.34). To gain insight into possible modes of collateral sensitivity, we performed in silico molecular docking studies of honokiol to EGFR and EGFR-related downstream signal proteins. Honokiol bound with comparable binding energies to EGFR (-7.30 ± 0.01 kcal/mol) as the control drugs erlotinib (-7.50 ± 0.30 kcal/mol) and gefitinib (-8.30 ± 0.10 kcal/mol). Similar binding affinities of AKT, MEK1, MEK2, STAT3 and mTOR were calculated for honokiol (range from -9.0 ± 0.01 to 7.40 ± 0.01 kcal/mol) compared to corresponding control inhibitor compounds for these signal transducers. This indicates that collateral sensitivity of EGFR-transfectant cells towards honokiol may be due to binding to EGFR and downstream signal transducers. COMPARE and hierarchical cluster analyses of microarray-based transcriptomic mRNA expression data of 59 tumor cell lines revealed a specific gene expression profile predicting sensitivity or resistance towards honokiol.

Addresses

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

Autoren

Mohamed Saeed
Victor Kuete
Onat Kadioglu
Jonas Börtzler
Hassan Khalid
Henry Johannes Greten
Thomas Efferth
Thomas Efferth

DOI

10.1016/j.phymed.2014.07.011

eISSN

1618-095X

Externe Identifier

PubMed Identifier: 25442261

Open access

false

ISSN

0944-7113

Ausgabe der Veröffentlichung

12

Zeitschrift

Phytomedicine : international journal of phytotherapy and phytopharmacology

Schlüsselwörter

Cell Line, Tumor
Humans
Magnolia
Lignans
Biphenyl Compounds
ATP-Binding Cassette Transporters
Neoplasm Proteins
Antineoplastic Agents, Phytogenic
Oligonucleotide Array Sequence Analysis
Pharmacogenetics
Drug Resistance, Multiple
Signal Transduction
Drug Resistance, Neoplasm
Tumor Suppressor Protein p53
Transcriptome
Molecular Docking Simulation
ErbB Receptors
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP Binding Cassette Transporter, Subfamily B

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

1525 - 1533

Datum der Veröffentlichung

2014

Status

Published

Datum der Datenerfassung

2014

Titel

Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking.

Sub types

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

Ausgabe der Zeitschrift

21

Data source: Europe PubMed Central

Abstract

A main problem in oncology is the development of drug-resistance. Some plant-derived lignans are established in cancer therapy, e.g. the semisynthetic epipodophyllotoxins etoposide and teniposide. Their activity is, unfortunately, hampered by the ATP-binding cassette (ABC) efflux transporter, P-glycoprotein. Here, we investigated the bisphenolic honokiol derived from Magnolia officinalis. P-glycoprotein-overexpressing CEM/ADR5000 cells were not cross-resistant to honokiol, but MDA-MB-231 BRCP cells transfected with another ABC-transporter, BCRP, revealed 3-fold resistance. Further drug resistance mechanisms analyzed study was the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). HCT116 p53(-/-) did not reveal resistance to honokiol, and EGFR-transfected U87.MG EGFR cells were collateral sensitive compared to wild-type cells (degree of resistance: 0.34). To gain insight into possible modes of collateral sensitivity, we performed in silico molecular docking studies of honokiol to EGFR and EGFR-related downstream signal proteins. Honokiol bound with comparable binding energies to EGFR (-7.30 ± 0.01 kcal/mol) as the control drugs erlotinib (-7.50 ± 0.30 kcal/mol) and gefitinib (-8.30 ± 0.10 kcal/mol). Similar binding affinities of AKT, MEK1, MEK2, STAT3 and mTOR were calculated for honokiol (range from -9.0 ± 0.01 to 7.40 ± 0.01 kcal/mol) compared to corresponding control inhibitor compounds for these signal transducers. This indicates that collateral sensitivity of EGFR-transfectant cells towards honokiol may be due to binding to EGFR and downstream signal transducers. COMPARE and hierarchical cluster analyses of microarray-based transcriptomic mRNA expression data of 59 tumor cell lines revealed a specific gene expression profile predicting sensitivity or resistance towards honokiol.

Date of acceptance

2014

Autoren

Mohamed Saeed
Victor Kuete
Onat Kadioglu
Jonas Börtzler
Hassan Khalid
Henry Johannes Greten
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/25442261

DOI

10.1016/j.phymed.2014.07.011

eISSN

1618-095X

Ausgabe der Veröffentlichung

12

Zeitschrift

Phytomedicine

Schlüsselwörter

ABC-transporter
Cluster analysis
Kinase inhibitor
Magnolia officinalis Honokiol
Microarrays
Multidrug resistance
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Antineoplastic Agents, Phytogenic
Biphenyl Compounds
Cell Line, Tumor
Drug Resistance, Multiple
Drug Resistance, Neoplasm
ErbB Receptors
Humans
Lignans
Magnolia
Molecular Docking Simulation
Neoplasm Proteins
Oligonucleotide Array Sequence Analysis
Pharmacogenetics
Signal Transduction
Transcriptome
Tumor Suppressor Protein p53

Sprache

eng

Country

Germany

Paginierung

1525 - 1533

PII

S0944-7113(14)00297-9

Datum der Veröffentlichung

2014

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking.

Sub types

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

Ausgabe der Zeitschrift

21

Data source: PubMed

Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking

Tools