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

Autor: Christopher Watson, Nazmul Huda, Melanie E. Alpuche, David Gilley, Jeremy B. Shapiro, Peter A. Crooks, Ronald H. Shapiro, Helen Chin-Sinex, Marc S. Mendonca, Imade E. Imasuen-Williams, William T. Turchan, Neil C. Estabrook, Gabriel Rangel
Rok vydání: 2017
Předmět:
Cyclin-Dependent Kinase Inhibitor p21
Male
0301 basic medicine
Radiation-Sensitizing Agents
DNA Repair
medicine.medical_treatment
Mice
Nude
Antineoplastic Agents
Biology
Radiation Tolerance
Biochemistry
Article
Mice
03 medical and health sciences
Prostate cancer
chemistry.chemical_compound
0302 clinical medicine
DU145
In vivo
Prostate
Cell Line
Tumor
Physiology (medical)
medicine
Animals
Humans
DNA Breaks
Double-Stranded
Parthenolide
bcl-2-Associated X Protein
X-Rays
NF-kappa B
Prostatic Neoplasms
medicine.disease
Xenograft Model Antitumor Assays
Gene Expression Regulation
Neoplastic
Radiation therapy
030104 developmental biology
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
chemistry
030220 oncology & carcinogenesis
Immunology
Cancer cell
Cancer research
Radiosensitizing Agent
Sesquiterpenes
BH3 Interacting Domain Death Agonist Protein
Signal Transduction
Zdroj: Free Radical Biology and Medicine. 112:318-326
ISSN: 0891-5849
DOI: 10.1016/j.freeradbiomed.2017.08.001
Popis: 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.
Databáze: OpenAIRE
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