Pharmacogenomic and molecular docking studies on the cytotoxicity of the natural steroid wortmannin against multidrug-resistant tumor cells

Autoren

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

DOI

10.1016/j.phymed.2014.11.011

ISSN

0944-7113

Ausgabe der Veröffentlichung

1

Zeitschrift

Phytomedicine

Sprache

en

Paginierung

120 - 127

Datum der Veröffentlichung

2015

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.phymed.2014.11.011

Datum der Datenerfassung

2022

Titel

Pharmacogenomic and molecular docking studies on the cytotoxicity of the natural steroid wortmannin against multidrug-resistant tumor cells

Ausgabe der Zeitschrift

22

Data source: Crossref

Abstract

Wortmannin is a cytotoxic compound derived from the endophytic fungi Fusarium oxysporum, Penicillium wortmannii and Penicillium funiculosum that occurs in many plants, including medicinal herbs. The rationale to develop novel anticancer drugs is the frequent development of tumor resistance to the existing antineoplasic agents. Therefore, it is mandatory to analyze resistance mechanisms of novel drug candidates such as wortmannin as well to bring effective drugs into the clinic that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients. In the present project, we found that P-glycoprotein-overexpressing tumor cells displaying the classical multidrug resistance phenotype toward standard anticancer drugs were not cross-resistant to wortmannin. Furthermore, three point-mutated PIK3CA protein structures revealed similar binding energies to wortmannin than wild-type PIK3CA. This protein is the primary target of wortmannin and part of the PI3K/AKT/mTOR signaling pathway. PIK3CA mutations are known to be associated with worse response to therapy and shortened its activity toward wild-type and mutant PIK3CA with similar efficacy.

Addresses

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.

Autoren

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

DOI

10.1016/j.phymed.2014.11.011

eISSN

1618-095X

Externe Identifier

PubMed Identifier: 25636880

Open access

false

ISSN

0944-7113

Ausgabe der Veröffentlichung

1

Zeitschrift

Phytomedicine : international journal of phytotherapy and phytopharmacology

Schlüsselwörter

Cell Line, Tumor
Humans
Androstadienes
Antineoplastic Agents
Oligonucleotide Array Sequence Analysis
Cluster Analysis
Pharmacogenetics
Drug Resistance, Multiple
Signal Transduction
Drug Resistance, Neoplasm
Phosphatidylinositol 3-Kinases
Class I Phosphatidylinositol 3-Kinases
Molecular Docking Simulation
Wortmannin
ATP Binding Cassette Transporter, Subfamily B

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

120 - 127

Datum der Veröffentlichung

2015

Status

Published

Datum der Datenerfassung

2015

Titel

Pharmacogenomic and molecular docking studies on the cytotoxicity of the natural steroid wortmannin against multidrug-resistant tumor cells.

Sub types

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

Ausgabe der Zeitschrift

22

Data source: Europe PubMed Central

Abstract

Wortmannin is a cytotoxic compound derived from the endophytic fungi Fusarium oxysporum, Penicillium wortmannii and Penicillium funiculosum that occurs in many plants, including medicinal herbs. The rationale to develop novel anticancer drugs is the frequent development of tumor resistance to the existing antineoplasic agents. Therefore, it is mandatory to analyze resistance mechanisms of novel drug candidates such as wortmannin as well to bring effective drugs into the clinic that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients. In the present project, we found that P-glycoprotein-overexpressing tumor cells displaying the classical multidrug resistance phenotype toward standard anticancer drugs were not cross-resistant to wortmannin. Furthermore, three point-mutated PIK3CA protein structures revealed similar binding energies to wortmannin than wild-type PIK3CA. This protein is the primary target of wortmannin and part of the PI3K/AKT/mTOR signaling pathway. PIK3CA mutations are known to be associated with worse response to therapy and shortened its activity toward wild-type and mutant PIK3CA with similar efficacy.

Date of acceptance

2014

Autoren

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

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/25636880

DOI

10.1016/j.phymed.2014.11.011

eISSN

1618-095X

Ausgabe der Veröffentlichung

1

Zeitschrift

Phytomedicine

Schlüsselwörter

ABC-transporter
Cluster analysis
Drug resistance
Fusarium oxysporum
Kinase inhibitor
Microarrays
Molecular docking
Wortmannin
ATP Binding Cassette Transporter, Subfamily B
Androstadienes
Antineoplastic Agents
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Cluster Analysis
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Humans
Molecular Docking Simulation
Oligonucleotide Array Sequence Analysis
Pharmacogenetics
Phosphatidylinositol 3-Kinases
Signal Transduction
Wortmannin

Sprache

eng

Country

Germany

Paginierung

120 - 127

PII

S0944-7113(14)00392-4

Datum der Veröffentlichung

2015

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

Pharmacogenomic and molecular docking studies on the cytotoxicity of the natural steroid wortmannin against multidrug-resistant tumor cells.

Sub types

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

Ausgabe der Zeitschrift

22

Data source: PubMed

Pharmacogenomic and molecular docking studies on the cytotoxicity of the natural steroid wortmannin against multidrug-resistant tumor cells

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