DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo

Marc Mendonca, William T. Turchan, Melanie E. Alpuche, Christopher N. Watson, Neil C. Estabrook, Helen Chin-Sinex, Jeremy B. Shapiro, Imade E. Imasuen-Williams, Gabriel Rangel, David P. Gilley, Nazmul Huda, Peter A. Crooks, Ronald H. Shapiro

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide can inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with dimethylaminoparthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-κB binding activity and slows prostate cancer cell growth. We also show that DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair and also that DMAPT-induced radiosensitization is, at least partially, dependent upon the alteration of intracellular thiol reduction-oxidation chemistry. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer.

Original languageEnglish (US)
Pages (from-to)318-326
Number of pages9
JournalFree Radical Biology and Medicine
Volume112
DOIs
StatePublished - Nov 1 2017

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Radiotherapy
Heterografts
Tumors
Prostatic Neoplasms
Cells
X-Rays
X rays
Radiation-Sensitizing Agents
Neoplasms
Chemotherapy
Cell growth
Biological Products
Sulfhydryl Compounds
Repair
Transcription Factors
Biological Availability
Chemical activation
Derivatives
Radiation
Oxidation

Keywords

  • Comet assay
  • DMAPT
  • DNA double-strand break repair
  • DU145
  • NF-κB
  • PC-3
  • Split-dose repair
  • X-rays

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo. / Mendonca, Marc; Turchan, William T.; Alpuche, Melanie E.; Watson, Christopher N.; Estabrook, Neil C.; Chin-Sinex, Helen; Shapiro, Jeremy B.; Imasuen-Williams, Imade E.; Rangel, Gabriel; Gilley, David P.; Huda, Nazmul; Crooks, Peter A.; Shapiro, Ronald H.

In: Free Radical Biology and Medicine, Vol. 112, 01.11.2017, p. 318-326.

Research output: Contribution to journalArticle

Mendonca, M, Turchan, WT, Alpuche, ME, Watson, CN, Estabrook, NC, Chin-Sinex, H, Shapiro, JB, Imasuen-Williams, IE, Rangel, G, Gilley, DP, Huda, N, Crooks, PA & Shapiro, RH 2017, 'DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo', Free Radical Biology and Medicine, vol. 112, pp. 318-326. https://doi.org/10.1016/j.freeradbiomed.2017.08.001
Mendonca, Marc ; Turchan, William T. ; Alpuche, Melanie E. ; Watson, Christopher N. ; Estabrook, Neil C. ; Chin-Sinex, Helen ; Shapiro, Jeremy B. ; Imasuen-Williams, Imade E. ; Rangel, Gabriel ; Gilley, David P. ; Huda, Nazmul ; Crooks, Peter A. ; Shapiro, Ronald H. / DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo. In: Free Radical Biology and Medicine. 2017 ; Vol. 112. pp. 318-326.
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AU - Watson, Christopher N.

AU - Estabrook, Neil C.

AU - Chin-Sinex, Helen

AU - Shapiro, Jeremy B.

AU - Imasuen-Williams, Imade E.

AU - Rangel, Gabriel

AU - Gilley, David P.

AU - Huda, Nazmul

AU - Crooks, Peter A.

AU - Shapiro, Ronald H.

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