Upregulation of intrinsic apoptotic pathway in NSAIDs mediated chemoprevention of experimental lung carcinogenesis.
BACKGROUND
Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of cyclooxygenase-2 (COX-2), which is overexpressed in cancer. The role of COX-2 and apoptosis were evaluated in 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung cancer in rat and chemoprevention with indomethacin, a traditional NSAID and etoricoxib, a selective COX-2 inhibitor.


METHODS
The animals were divided into Control, DMBA, DMBA+ indomethacin and DMBA+ etoricoxib groups. They received a single intratracheal instillation of DMBA while NSAIDs were given orally daily for 32 weeks. Besides morphology and histology of lungs, RT-PCR, western blots and immunohistochemistry were performed for the expression of apoptotic proteins and COX enzymes. Apoptosis was studied by DNA fragmentation and fluorescent staining.


RESULTS
The occurrence of tumors and lesions was noted in the DMBA animals, besides constricted alveolar spaces and hyperplasia. COX-1 was found to be uniformly expressed while COX-2 level was raised significantly in DMBA group. The apoptotic proteins, apaf-1, caspase-9 and caspase-3 were highly diminished in DMBA group but restored to normal level in NSAIDs groups. Also, apoptosis was suppressed in carcinogen group by DNA fragmentation analysis and fluorescent staining of the lung cells while co-administration of NSAIDs along with DMBA led to the restoration of apoptosis.


CONCLUSIONS
DMBA administration to the rats led to tumorigenesis in the lungs, had no effects on COX-1 expression, while elevating the COX-2 levels and suppressing apoptosis. The treatment with NSAIDs led to the amelioration of these effects. However, etoricoxib which is a COX-2 specific inhibitor, was found to be more effective than the traditional NSAID, indomethacin.
Department of Biophysics, Panjab University, Chandigarh-160014, India.
Shruti
S
Setia
Sankar N
SN
Sanyal
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D000077613:Etoricoxib; D005260:Female; D007213:Indomethacin / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011725:Pyridines; D013450:Sulfones; D015127:9,10-Dimethyl-1,2-benzanthracene; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000077613:Etoricoxib; D007213:Indomethacin