Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy

Autoren

T EFFERTH

DOI

10.1016/j.drup.2005.04.003

ISSN

1368-7646

Ausgabe der Veröffentlichung

1-2

Zeitschrift

Drug Resistance Updates

Sprache

en

Paginierung

85 - 97

Datum der Veröffentlichung

2005

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.drup.2005.04.003

Datum der Datenerfassung

2019

Titel

Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy

Ausgabe der Zeitschrift

8

Data source: Crossref

Abstract

In addition to their well-known anti-malarial activity, artemisinin and its derivatives (1,2,4-trioxanes) possess potent activity against tumor cells in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. These genes are from classes with different biological function; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Anti-oxidant stress genes (thioredoxin, catalase, gamma-glutamyl-cysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines over-expressing genes that confer resistance to established anti-tumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that this drug has a different target and is not subject to multidrug resistance. The Plasmodium translationally controlled tumor protein (TCTP) represents a known target protein of artemisinin and its derivatives in the malaria parasite. The microarray-based mRNA expression of human TCTP correlated with sensitivity to artesunate in tumor cells, suggesting that human TCTP contributes to response of tumor cells to the drug. The multi-factorial nature of cellular response to artemisinin and its derivatives may be beneficial to treat otherwise drug-resistant tumors and may explain why resistance development has not been observed in either cancer or malaria.

Addresses

German Cancer Research Center, M070, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. thomas.efferth@web.de

Autoren

Thomas Efferth
Thomas Efferth

DOI

10.1016/j.drup.2005.04.003

eISSN

1532-2084

Externe Identifier

PubMed Identifier: 15878303

Open access

false

ISSN

1368-7646

Ausgabe der Veröffentlichung

1-2

Zeitschrift

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

Schlüsselwörter

Animals
Humans
Neoplasms
Sesquiterpenes
Artemisinins
Heterocyclic Compounds
Antimalarials
Oligonucleotide Array Sequence Analysis
Cluster Analysis
Pharmacogenetics
Drug Resistance, Multiple
Apoptosis
Oxidative Stress
Tumor Protein, Translationally-Controlled 1

Sprache

eng

Medium

Print

Paginierung

85 - 97

Datum der Veröffentlichung

2005

Status

Published

Datum der Datenerfassung

2005

Titel

Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy.

Sub types

Review
Journal Article

Ausgabe der Zeitschrift

8

Data source: Europe PubMed Central

Abstract

In addition to their well-known anti-malarial activity, artemisinin and its derivatives (1,2,4-trioxanes) possess potent activity against tumor cells in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. These genes are from classes with different biological function; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Anti-oxidant stress genes (thioredoxin, catalase, gamma-glutamyl-cysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines over-expressing genes that confer resistance to established anti-tumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that this drug has a different target and is not subject to multidrug resistance. The Plasmodium translationally controlled tumor protein (TCTP) represents a known target protein of artemisinin and its derivatives in the malaria parasite. The microarray-based mRNA expression of human TCTP correlated with sensitivity to artesunate in tumor cells, suggesting that human TCTP contributes to response of tumor cells to the drug. The multi-factorial nature of cellular response to artemisinin and its derivatives may be beneficial to treat otherwise drug-resistant tumors and may explain why resistance development has not been observed in either cancer or malaria.

Date of acceptance

2005

Autoren

Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/15878303

DOI

10.1016/j.drup.2005.04.003

ISSN

1368-7646

Ausgabe der Veröffentlichung

1-2

Zeitschrift

Drug Resist Updat

Schlüsselwörter

Animals
Antimalarials
Apoptosis
Artemisinins
Cluster Analysis
Drug Resistance, Multiple
Heterocyclic Compounds
Humans
Neoplasms
Oligonucleotide Array Sequence Analysis
Oxidative Stress
Pharmacogenetics
Sesquiterpenes
Tumor Protein, Translationally-Controlled 1

Sprache

eng

Country

Scotland

Paginierung

85 - 97

PII

S1368-7646(05)00029-4

Datum der Veröffentlichung

2005

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2005

Titel

Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy.

Sub types

Journal Article
Review

Ausgabe der Zeitschrift

8

Data source: PubMed

Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy

Tools