First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases

Abstract

AbstractDespite progress in treatment, progressive non–small cell lung cancer (NSCLC) still limits survival dramatically, and novel therapeutic compounds are needed. Initial investigations suggest that artesunate (ART), an antimalarial drug, has antiproliferative capacities. However, antiinvasive and antimetastatic properties of ART in cancer have never been explored. Therefore, this first study was performed to (i) investigate if ART is able to inhibit invasion and metastasis in NSCLC and (ii) to identify first molecular targets and mechanisms mediating this ability. ART significantly impaired matrigel invasion of 6 NSCLC cell lines and inhibited urokinase‐type plasminogen activator (u‐PA) activity, ‐protein and ‐mRNA expression. Furthermore, in a PCR‐metastasis array, ART inhibited the expression of several matrix metalloproteinases (MMPs), especially MMP‐2 and MMP‐7 mRNA/protein. In luciferase reporter assays, ART downregulated MMP‐2‐, MMP‐7‐ and u‐PA‐promoter/‐enhancer activity, in parallel to AP‐1‐ and NF‐kB‐transactivation. Si‐RNA knockdown of u‐PA, MMP‐2 and MMP‐7 abolished ART's ability to inhibit invasion, confirming their role as essential mediators. In vivo, ART significantly impaired primary tumor growth and metastasis in the chicken embryo metastasis (CAM) model. In conclusion, this is the first study to show that ART considerably suppresses invasion and metastasis in NSCLC, specifically targeting transcription of u‐PA, MMP‐2 and MMP‐7, prompting immediate studies on ART as a novel therapeutic in NSCLC.

Autoren

Suhail Ahmed Kabeer Rasheed
Thomas Efferth
Irfan Ahmed Asangani
Heike Allgayer

DOI

10.1002/ijc.25315

eISSN

1097-0215

ISSN

0020-7136

Ausgabe der Veröffentlichung

6

Zeitschrift

International Journal of Cancer

Sprache

en

Online publication date

2010

Paginierung

1475 - 1485

Datum der Veröffentlichung

2010

Status

Published

Herausgeber

Wiley

Herausgeber URL

http://dx.doi.org/10.1002/ijc.25315

Datum der Datenerfassung

2023

Titel

First evidence that the antimalarial drug artesunate inhibits invasion and <i>in vivo</i> metastasis in lung cancer by targeting essential extracellular proteases

Ausgabe der Zeitschrift

127

Data source: Crossref

Abstract

Despite progress in treatment, progressive non-small cell lung cancer (NSCLC) still limits survival dramatically, and novel therapeutic compounds are needed. Initial investigations suggest that artesunate (ART), an antimalarial drug, has antiproliferative capacities. However, antiinvasive and antimetastatic properties of ART in cancer have never been explored. Therefore, this first study was performed to (i) investigate if ART is able to inhibit invasion and metastasis in NSCLC and (ii) to identify first molecular targets and mechanisms mediating this ability. ART significantly impaired matrigel invasion of 6 NSCLC cell lines and inhibited urokinase-type plasminogen activator (u-PA) activity, -protein and -mRNA expression. Furthermore, in a PCR-metastasis array, ART inhibited the expression of several matrix metalloproteinases (MMPs), especially MMP-2 and MMP-7 mRNA/protein. In luciferase reporter assays, ART downregulated MMP-2-, MMP-7- and u-PA-promoter/-enhancer activity, in parallel to AP-1- and NF-kB-transactivation. Si-RNA knockdown of u-PA, MMP-2 and MMP-7 abolished ART's ability to inhibit invasion, confirming their role as essential mediators. In vivo, ART significantly impaired primary tumor growth and metastasis in the chicken embryo metastasis (CAM) model. In conclusion, this is the first study to show that ART considerably suppresses invasion and metastasis in NSCLC, specifically targeting transcription of u-PA, MMP-2 and MMP-7, prompting immediate studies on ART as a novel therapeutic in NSCLC.

Addresses

Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Medical Faculty Mannheim, University of Heidelberg and German Cancer Research Center DKFZ, Heidelberg, Germany.

Autoren

Suhail Ahmed Kabeer Rasheed
Thomas Efferth
Thomas Efferth
Irfan Ahmed Asangani
Heike Allgayer

DOI

10.1002/ijc.25315

eISSN

1097-0215

Externe Identifier

PubMed Identifier: 20232396

Open access

false

ISSN

0020-7136

Ausgabe der Veröffentlichung

6

Zeitschrift

International journal of cancer

Schlüsselwörter

Chick Embryo
Animals
Humans
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Neoplasm Invasiveness
Neoplasm Metastasis
Artemisinins
Matrix Metalloproteinases
RNA, Messenger
Antimalarials
Enzyme-Linked Immunosorbent Assay
Gene Expression Profiling
Polymerase Chain Reaction
Cell Proliferation
Urokinase-Type Plasminogen Activator
Artesunate

Sprache

eng

Medium

Print

Paginierung

1475 - 1485

Datum der Veröffentlichung

2010

Status

Published

Datum der Datenerfassung

2010

Titel

First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases.

Sub types

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

Ausgabe der Zeitschrift

127

Data source: Europe PubMed Central

Abstract

Despite progress in treatment, progressive non-small cell lung cancer (NSCLC) still limits survival dramatically, and novel therapeutic compounds are needed. Initial investigations suggest that artesunate (ART), an antimalarial drug, has antiproliferative capacities. However, antiinvasive and antimetastatic properties of ART in cancer have never been explored. Therefore, this first study was performed to (i) investigate if ART is able to inhibit invasion and metastasis in NSCLC and (ii) to identify first molecular targets and mechanisms mediating this ability. ART significantly impaired matrigel invasion of 6 NSCLC cell lines and inhibited urokinase-type plasminogen activator (u-PA) activity, -protein and -mRNA expression. Furthermore, in a PCR-metastasis array, ART inhibited the expression of several matrix metalloproteinases (MMPs), especially MMP-2 and MMP-7 mRNA/protein. In luciferase reporter assays, ART downregulated MMP-2-, MMP-7- and u-PA-promoter/-enhancer activity, in parallel to AP-1- and NF-kB-transactivation. Si-RNA knockdown of u-PA, MMP-2 and MMP-7 abolished ART's ability to inhibit invasion, confirming their role as essential mediators. In vivo, ART significantly impaired primary tumor growth and metastasis in the chicken embryo metastasis (CAM) model. In conclusion, this is the first study to show that ART considerably suppresses invasion and metastasis in NSCLC, specifically targeting transcription of u-PA, MMP-2 and MMP-7, prompting immediate studies on ART as a novel therapeutic in NSCLC.

Autoren

Suhail Ahmed Kabeer Rasheed
Thomas Efferth
Irfan Ahmed Asangani
Heike Allgayer

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/20232396

DOI

10.1002/ijc.25315

eISSN

1097-0215

Ausgabe der Veröffentlichung

6

Zeitschrift

Int J Cancer

Schlüsselwörter

Animals
Antimalarials
Artemisinins
Artesunate
Carcinoma, Non-Small-Cell Lung
Cell Proliferation
Chick Embryo
Enzyme-Linked Immunosorbent Assay
Gene Expression Profiling
Humans
Lung Neoplasms
Matrix Metalloproteinases
Neoplasm Invasiveness
Neoplasm Metastasis
Polymerase Chain Reaction
RNA, Messenger
Urokinase-Type Plasminogen Activator

Sprache

eng

Country

United States

Paginierung

1475 - 1485

Datum der Veröffentlichung

2010

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2010

Titel

First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases.

Sub types

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

Ausgabe der Zeitschrift

127

Data source: PubMed

First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases

Tools