Inhibition of NF-kappaB pathway in grape seed extract-induced apoptotic death of human prostate carcinoma DU145 cells.
The alarmingly high rate of prostate cancer (PCA) mortality as well as the limited success in the treatment of advanced PCA suggest that additional approaches are needed to control PCA growth and its metastatic potential. A constitutive activation of NF-kappaB family of transcription factors is known to play a major role in chemotherapy resistance in advanced PCA. In recent studies we showed that grape seed extract (GSE) inhibits advanced human PCA growth and induces apoptosis in cell culture and in nude mice. Accordingly, here we assessed the effect of GSE on constitutive and TNFalpha-induced NF-kappaB DNA binding activity and apoptotic death in advanced human prostate carcinoma DU145 cells. Constitutive and TNFalpha-induced NF-kappaB DNA binding activity was inhibited by GSE at doses > or =50 microg/ml and treatments for > or =12 h. This was accompanied by inhibition of IkappaBalpha phosphorylation and IKKalpha kinase activity. A strong induction of apoptosis (P<0.01) was also observed following GSE treatment, while a combination with TNFalpha strongly potentiated apoptosis induction. Our results indicate the potential of developing GSE as an effective cancer therapeutic agent, both alone and in combination with TNFalpha-based chemotherapy of advanced human prostate carcinoma that might prove to be a more effective and less toxic alternative in clinical therapy of PCA.
Dhanalakshmi
Sivanandhan
S
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA.
Agarwal
Rajesh
R
Agarwal
Chapla
C
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051550:I-kappa B Kinase; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009362:Neoplasm Metastasis; D009841:Oligonucleotides / Q000737:chemistry; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012639:Seeds / Q000378:metabolism*; D013997:Time Factors; D027843:Vitis / Q000378:metabolism*
D016328:NF-kappa B; D009841:Oligonucleotides; D010936:Plant Extracts; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse