title: Administration of IκB-kinase inhibitor PS1145 enhances apoptosis in DMBA-induced tumor in male Wistar rats.
abstract: Nuclear factor kappa-B (NF-κB), a key anti-apoptotic factor, plays a critical role in tumor cell growth, metastasis, and angiogenesis. The transcriptional activity of NF-κB is normally suppressed in the cytoplasm due to its association with a natural inhibitor molecule IκB. Phosphorylation of the IκB at Ser 32 and Ser 36 by the IκB kinase complex (IKK) marks the degradation of the molecule by 26S proteasome. As NF-κB is constitutively activated in most of the tumor cells, inhibition of the activities of IKK may significantly sensitize the tumor cells to apoptosis. In the present study, we investigated the effect of IκB kinase-specific blocker PS1145 on DMBA-induced skin tumor of male Wistar rats. We examined the apoptotic effect of PS1145 on DMBA-induced tumor by various histopathological and molecular techniques. Our results demonstrate the significant expression of major pro-apoptotic genes like caspases 2, 3, 8, 9, and p53 in PS1145-treated tumor bearing group at mRNA levels as well as significant (P < 0.05) down regulation in the expression levels of NF-κB and VEGF, the major pro-inflammatory and pro-angiogenic factors, respectively. The histopathological examination showed that the tumor progression, mitotic, AgNOR, and PCNA indices were significantly reduced in PS1145 treatment groups as compared to PBS control on day 28 of post-treatment. Furthermore, significant increase in TUNEL positive nuclei and observation of peculiar apoptotic nuclei in transmission electron microscopy were seen in PS1145 treatment group. We conclude that intravenous application of PS1145 promotes direct apoptosis in DMBA-induced skin tumor in male Wistar rats by blocking NF-κB and VEGF activities.
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: R S
authors.initials: RS
authors.lastname: Rajmani
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Ravi Kumar
authors.initials: RK
authors.lastname: Gandham
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Shishir Kumar
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Aditya P
authors.initials: AP
authors.lastname: Sahoo
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Prafull Kumar
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Shikha
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Uttara
authors.initials: U
authors.lastname: Chaturvedi
authors.affiliation: Molecular Biology Laboratory, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Tiwari
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D016328:NF-kappa B; C456319:PS1145; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D015127:9,10-Dimethyl-1,2-benzanthracene; D051550:I-kappa B Kinase
keywords: IKK kinases; IκBs; NF-κB; PS1145; apoptosis; cancer; tumor