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.