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Departments of ¹ Medicine, ² Pathology, ³ Surgery, and ⁴ Biochemistry and Molecular Biology, ⁵ Walther Oncology Center, Indiana University School of Medicine; ⁶ Walther Cancer Institute, Indianapolis, Indiana; and ⁷ College of Pharmacy, The University of Iowa, Iowa City, Iowa

Requests for reprints: Harikrishna Nakshatri, R-202, Indiana Cancer Research Institute, 1044 West Walnut Street, Indianapolis, IN 46202. Phone: 317-278-2238; Fax: 317-274-0396. E-mail: hnakshat{at}iupui.edu

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 B (NF-B) 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 GADD45ß1 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-B 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-B.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: H. Nakshatri is a Marian J. Morrison Investigator in Breast Cancer Research.

Received 1/31/05; revised 3/26/05; accepted 4/11/05.