TY - JOUR
T1 - The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer
AU - Sweeney, Christopher J.
AU - Mehrotra, Sanjana
AU - Sadaria, Miral R.
AU - Kumar, Suresh
AU - Shortle, Nicholas H.
AU - Roman, Yaritzabel
AU - Sheridan, Carol
AU - Campbell, Robert A.
AU - Murry, Daryl J.
AU - Badve, Sunil
AU - Nakshatri, Harikrishna
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/6
Y1 - 2005/6
N2 - Parthenolide, a sesquiterpene lactone, shows antitumor activity in vitro, which correlates with its ability to inhibit the DNA binding of the antiapoptotic transcription factor nuclear factor κB (NF-κB) and activation of the c-Jun NH2-terminal kinase. In this study, we investigated the chemosensitizing activity of parthenolide in vitro as well as in MDA-MB-231 cell-derived xenograft metastasis model of breast cancer. HBL-100 and MDA-MB-231 cells were used to measure the antitumor and chemosensitizing activity of parthenolide in vitro. Parthenolide was effective either alone or in combination with docetaxel in reducing colony formation, inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45β1 in vitro. In an adjuvant setting, animals treated with parthenolide and docetaxel combination showed significantly enhanced survival compared with untreated animals or animals treated with either drug. The enhanced survival in the combination arm was associated with reduced lung metastases. In addition, nuclear NF-κB levels were lower in residual tumors and lung metastasis of animals treated with parthenolide, docetaxel, or both. In the established orthotopic model, there was a trend toward slower growth in the parthenolide-treated animals but no statistically significant findings were seen. These results for the first time reveal the significant in vivo chemosensitizing properties of parthenolide in the metastatic breast cancer setting and support the contention that metastases are very reliant on activation of NF-κB.
AB - Parthenolide, a sesquiterpene lactone, shows antitumor activity in vitro, which correlates with its ability to inhibit the DNA binding of the antiapoptotic transcription factor nuclear factor κB (NF-κB) and activation of the c-Jun NH2-terminal kinase. In this study, we investigated the chemosensitizing activity of parthenolide in vitro as well as in MDA-MB-231 cell-derived xenograft metastasis model of breast cancer. HBL-100 and MDA-MB-231 cells were used to measure the antitumor and chemosensitizing activity of parthenolide in vitro. Parthenolide was effective either alone or in combination with docetaxel in reducing colony formation, inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45β1 in vitro. In an adjuvant setting, animals treated with parthenolide and docetaxel combination showed significantly enhanced survival compared with untreated animals or animals treated with either drug. The enhanced survival in the combination arm was associated with reduced lung metastases. In addition, nuclear NF-κB levels were lower in residual tumors and lung metastasis of animals treated with parthenolide, docetaxel, or both. In the established orthotopic model, there was a trend toward slower growth in the parthenolide-treated animals but no statistically significant findings were seen. These results for the first time reveal the significant in vivo chemosensitizing properties of parthenolide in the metastatic breast cancer setting and support the contention that metastases are very reliant on activation of NF-κB.
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U2 - 10.1158/1535-7163.MCT-05-0030
DO - 10.1158/1535-7163.MCT-05-0030
M3 - Article
C2 - 15956258
AN - SCOPUS:21344454493
VL - 4
SP - 1004
EP - 1012
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 6
ER -