Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells

Beatrice Bachmeier, Iduna Fichtner, Peter H. Killian, Emanuel Kronski, Ulrich Pfeffer, Thomas Efferth

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate, clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of artesunate in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, artesunate induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, artesunate was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP-1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of artesunate in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that artesunate induces resistance in highly metastatic breast tumors.

Original languageEnglish
Article numbere20550
JournalPLoS One
Volume6
Issue number5
DOIs
Publication statusPublished - 2011

Fingerprint

breast neoplasms
Cells
Tumors
Breast Neoplasms
neoplasms
Neoplasms
Chemical activation
Apoptosis
apoptosis
Chemotherapy
Ants
interstitial collagenase
Second Primary Neoplasms
Drug and Narcotic Control
Transcription Factor AP-1
Antimalarials
therapeutics
Transcription
Cytotoxicity
doxorubicin

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Bachmeier, B., Fichtner, I., Killian, P. H., Kronski, E., Pfeffer, U., & Efferth, T. (2011). Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells. PLoS One, 6(5), [e20550]. https://doi.org/10.1371/journal.pone.0020550

Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells. / Bachmeier, Beatrice; Fichtner, Iduna; Killian, Peter H.; Kronski, Emanuel; Pfeffer, Ulrich; Efferth, Thomas.

In: PLoS One, Vol. 6, No. 5, e20550, 2011.

Research output: Contribution to journalArticle

Bachmeier, B, Fichtner, I, Killian, PH, Kronski, E, Pfeffer, U & Efferth, T 2011, 'Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells', PLoS One, vol. 6, no. 5, e20550. https://doi.org/10.1371/journal.pone.0020550
Bachmeier, Beatrice ; Fichtner, Iduna ; Killian, Peter H. ; Kronski, Emanuel ; Pfeffer, Ulrich ; Efferth, Thomas. / Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells. In: PLoS One. 2011 ; Vol. 6, No. 5.
@article{5f4b3c63aaf74ee391829998e19538a7,
title = "Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells",
abstract = "Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate, clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of artesunate in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, artesunate induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, artesunate was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP-1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of artesunate in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that artesunate induces resistance in highly metastatic breast tumors.",
author = "Beatrice Bachmeier and Iduna Fichtner and Killian, {Peter H.} and Emanuel Kronski and Ulrich Pfeffer and Thomas Efferth",
year = "2011",
doi = "10.1371/journal.pone.0020550",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells

AU - Bachmeier, Beatrice

AU - Fichtner, Iduna

AU - Killian, Peter H.

AU - Kronski, Emanuel

AU - Pfeffer, Ulrich

AU - Efferth, Thomas

PY - 2011

Y1 - 2011

N2 - Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate, clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of artesunate in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, artesunate induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, artesunate was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP-1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of artesunate in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that artesunate induces resistance in highly metastatic breast tumors.

AB - Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate, clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of artesunate in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, artesunate induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, artesunate was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP-1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of artesunate in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that artesunate induces resistance in highly metastatic breast tumors.

UR - http://www.scopus.com/inward/record.url?scp=79957572444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79957572444&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0020550

DO - 10.1371/journal.pone.0020550

M3 - Article

C2 - 21637790

AN - SCOPUS:79957572444

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e20550

ER -