Restoring chemotherapy and hormonetherapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model

Rajasubramaniam Shanmugam, Vetrichelvan Jayaprakasan, Yesim Gokmen-Polar, Stephanie Kelich, Kathy D. Miller, Michele Yip-Schneider, Liang Cheng, Poornima Bhat-Nakshatri, George W. Sledge, Harikrishna Nakshatri, Qi Huang Zheng, Michael A. Miller, Timothy DeGrado, Gary D. Hutchins, Christopher J. Sweeney

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

BACKGROUND. Nuclear Factor kappa B (NFκB) is a eukaryotic transcription factor that is constitutively active in human cancers and can be inhibited by the naturally occurring sesquiterpene lactone, parthenolide (P). METHODS. The in vitro effects of P were assessed using the androgen independent cell line, CWR22Rv1, and human umbilical endothelial cells (HUVECs). The in vivo activity of P as a single agent and its ability to augment the efficacy of docetaxel and the anti-androgen, bicalutamide, were determined using the CWR22Rv1 xenograft model. RESULTS. Parthenolide at low micromolar concentration inhibited proliferation of CWR22Rv1 and HUVEC cells, promoted apoptosis and abrogated NFκB-DNA binding. Parthenolide downregulated anti-apoptotic genes under NFκB control, TRAF 1 and 2, and promoted sustained activation of c-jun-NH2 kinase (JNK). Parthenolide also augmented the in vivo efficacy of docetaxel and restored sensitivity to anti-androgen therapy. CONCLUSION. These studies demonstrate parthenolide's anti-tumor and anti-angiogenic activity, and its potential to augment the efficacy of chemotherapy and hormonal therapy.

Original languageEnglish (US)
Pages (from-to)1498-1511
Number of pages14
JournalProstate
Volume66
Issue number14
DOIs
StatePublished - Oct 1 2006

Keywords

  • Angiogenesis
  • Anti-tumor
  • NFκB
  • Parthenolide

ASJC Scopus subject areas

  • Oncology
  • Urology

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    Shanmugam, R., Jayaprakasan, V., Gokmen-Polar, Y., Kelich, S., Miller, K. D., Yip-Schneider, M., Cheng, L., Bhat-Nakshatri, P., Sledge, G. W., Nakshatri, H., Zheng, Q. H., Miller, M. A., DeGrado, T., Hutchins, G. D., & Sweeney, C. J. (2006). Restoring chemotherapy and hormonetherapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model. Prostate, 66(14), 1498-1511. https://doi.org/10.1002/pros.20482