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Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells

BACKGROUND: A major obstacle for successful cancer treatment often is the development of drug resistance in cancer cells during chemotherapy. Therefore, there is an urgent need for novel drugs with improved efficacy against tumor cells and with less toxicity on normal cells. Artesunate (ART), a powe...

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Autores principales: Efferth, Thomas, Giaisi, Marco, Merling, Annette, Krammer, Peter H., Li-Weber, Min
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933253/
https://www.ncbi.nlm.nih.gov/pubmed/17668070
http://dx.doi.org/10.1371/journal.pone.0000693
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author Efferth, Thomas
Giaisi, Marco
Merling, Annette
Krammer, Peter H.
Li-Weber, Min
author_facet Efferth, Thomas
Giaisi, Marco
Merling, Annette
Krammer, Peter H.
Li-Weber, Min
author_sort Efferth, Thomas
collection PubMed
description BACKGROUND: A major obstacle for successful cancer treatment often is the development of drug resistance in cancer cells during chemotherapy. Therefore, there is an urgent need for novel drugs with improved efficacy against tumor cells and with less toxicity on normal cells. Artesunate (ART), a powerful anti-malarial herbal compound, has been shown to inhibit growth of various tumor cell lines in vitro and of xenografted Kaposi's sarcoma in mice in vivo. However, the molecular mechanisms by which ART exerts its cytotoxicity have not been elucidated. The ART-class of anti-malarial compounds is attractive due to their activity against multidrug-resistant Plasmodium falciparum and Plasmodium vivax strains. Another salient feature of these compounds is the lack of severe side effects in malaria patients. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we used T-cell leukemias as a model system to study the molecular mechanisms of ART-induced apoptosis. The most typical anticancer drugs are DNA intercalators such as Doxorubicin. To investigate drug sensitivity and resistance, we chose a Doxorubicin-resistant leukemia cell line and investigated the killing effect of ART on these cells. We show that ART induces apoptosis in leukemic T cells mainly through the mitochondrial pathway via generation of reactive oxygen species (ROS), a mechanism different from Doxorubicin. This is confirmed by the fact that the antioxidant N-Acetyle-Cysteine (NAC) could completely block ROS generation and, consequently, inhibited ART-induced apoptosis. Therefore, ART can overcome the Doxorubicin-resistance and induce the Doxorubicin-resistant leukemia cells to undergo apoptosis. We also show that ART can synergize with Doxorubicin to enhance apoptotic cell death in leukemic T cells. This synergistic effect can be largely explained by the fact that ART and Doxorubicin use different killing mechanisms. CONCLUSIONS: Our studies raise the possibility to develop ART in combination with other established anticancer drugs which induce apoptosis through the pathways or mechanisms different from ART.
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spelling pubmed-19332532007-08-01 Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells Efferth, Thomas Giaisi, Marco Merling, Annette Krammer, Peter H. Li-Weber, Min PLoS One Research Article BACKGROUND: A major obstacle for successful cancer treatment often is the development of drug resistance in cancer cells during chemotherapy. Therefore, there is an urgent need for novel drugs with improved efficacy against tumor cells and with less toxicity on normal cells. Artesunate (ART), a powerful anti-malarial herbal compound, has been shown to inhibit growth of various tumor cell lines in vitro and of xenografted Kaposi's sarcoma in mice in vivo. However, the molecular mechanisms by which ART exerts its cytotoxicity have not been elucidated. The ART-class of anti-malarial compounds is attractive due to their activity against multidrug-resistant Plasmodium falciparum and Plasmodium vivax strains. Another salient feature of these compounds is the lack of severe side effects in malaria patients. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we used T-cell leukemias as a model system to study the molecular mechanisms of ART-induced apoptosis. The most typical anticancer drugs are DNA intercalators such as Doxorubicin. To investigate drug sensitivity and resistance, we chose a Doxorubicin-resistant leukemia cell line and investigated the killing effect of ART on these cells. We show that ART induces apoptosis in leukemic T cells mainly through the mitochondrial pathway via generation of reactive oxygen species (ROS), a mechanism different from Doxorubicin. This is confirmed by the fact that the antioxidant N-Acetyle-Cysteine (NAC) could completely block ROS generation and, consequently, inhibited ART-induced apoptosis. Therefore, ART can overcome the Doxorubicin-resistance and induce the Doxorubicin-resistant leukemia cells to undergo apoptosis. We also show that ART can synergize with Doxorubicin to enhance apoptotic cell death in leukemic T cells. This synergistic effect can be largely explained by the fact that ART and Doxorubicin use different killing mechanisms. CONCLUSIONS: Our studies raise the possibility to develop ART in combination with other established anticancer drugs which induce apoptosis through the pathways or mechanisms different from ART. Public Library of Science 2007-08-01 /pmc/articles/PMC1933253/ /pubmed/17668070 http://dx.doi.org/10.1371/journal.pone.0000693 Text en Efferth et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Efferth, Thomas
Giaisi, Marco
Merling, Annette
Krammer, Peter H.
Li-Weber, Min
Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells
title Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells
title_full Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells
title_fullStr Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells
title_full_unstemmed Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells
title_short Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells
title_sort artesunate induces ros-mediated apoptosis in doxorubicin-resistant t leukemia cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933253/
https://www.ncbi.nlm.nih.gov/pubmed/17668070
http://dx.doi.org/10.1371/journal.pone.0000693
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