The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer.
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 kappaB (NF-kappaB) and activation of the c-Jun NH(2)-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 GADD45beta1 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-kappaB 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-kappaB.
Sweeney
Christopher J
CJ
Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
Mehrotra
Sanjana
S
Sadaria
Miral R
MR
Kumar
Suresh
S
Shortle
Nicholas H
NH
Roman
Yaritzabel
Y
Sheridan
Carol
C
Campbell
Robert A
RA
Murry
Daryl J
DJ
Badve
Sunil
S
Nakshatri
Harikrishna
H
D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000077143:Docetaxel; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000378:metabolism; D007783:Lactones / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D015850:Interleukin-6; D016209:Interleukin-8; D007783:Lactones; D012717:Sesquiterpenes; D043823:Taxoids; D014409:Tumor Necrosis Factor-alpha; D000077143:Docetaxel; C002669:parthenolide; D007371:Interferon-gamma