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

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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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

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Heterografts
docetaxel
Prostatic Neoplasms
Hormones
Drug Therapy
Androgens
NF-kappa B
B-Form DNA
Umbilicus
Sesquiterpenes
Human Umbilical Vein Endothelial Cells
Lactones
Neoplasms
Transcription Factors
Phosphotransferases
Down-Regulation
Endothelial Cells
parthenolide
Apoptosis
Cell Line

Keywords

  • Angiogenesis
  • Anti-tumor
  • NFκB
  • Parthenolide

ASJC Scopus subject areas

  • Urology

Cite this

Restoring chemotherapy and hormonetherapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model. / Shanmugam, Rajasubramaniam; Jayaprakasan, Vetrichelvan; Polar, Yesim; Kelich, Stephanie; Miller, Kathy; Yip-Schneider, Michele; Cheng, Liang; Bhat-Nakshatri, Poornima; Sledge, George W.; Nakshatri, Harikrishna; Zheng, Qi-Huang; Miller, Michael A.; DeGrado, Timothy; Hutchins, Gary; Sweeney, Christopher J.

In: Prostate, Vol. 66, No. 14, 01.10.2006, p. 1498-1511.

Research output: Contribution to journalArticle

Shanmugam, Rajasubramaniam ; Jayaprakasan, Vetrichelvan ; Polar, Yesim ; Kelich, Stephanie ; Miller, Kathy ; Yip-Schneider, Michele ; Cheng, Liang ; Bhat-Nakshatri, Poornima ; Sledge, George W. ; Nakshatri, Harikrishna ; Zheng, Qi-Huang ; Miller, Michael A. ; DeGrado, Timothy ; Hutchins, Gary ; Sweeney, Christopher J. / Restoring chemotherapy and hormonetherapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model. In: Prostate. 2006 ; Vol. 66, No. 14. pp. 1498-1511.
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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.",
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AU - Shanmugam, Rajasubramaniam

AU - Jayaprakasan, Vetrichelvan

AU - Polar, Yesim

AU - Kelich, Stephanie

AU - Miller, Kathy

AU - Yip-Schneider, Michele

AU - Cheng, Liang

AU - Bhat-Nakshatri, Poornima

AU - Sledge, George W.

AU - Nakshatri, Harikrishna

AU - Zheng, Qi-Huang

AU - Miller, Michael A.

AU - DeGrado, Timothy

AU - Hutchins, Gary

AU - Sweeney, Christopher J.

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AB - 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.

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