Initiation of malignancy is dependent upon the basic ratio of cell proliferation and apoptosis. Many molecular proteins and pathways are responsible for the imbalance of proliferation and apoptosis ratio. For example, Akt is a key biomolecule which regulates the cell survival signals via various downstream pathways. One of those pathways is nuclear factor-κB activation which also regulates many downstream pathways that are essential for cell survival. Along with these anti-apoptotic pathways, cells do have a parallel mechanism to prevent malignancy with the help of the ligand-induced nuclear receptors, e.g., peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ has been found to be expressed in many cancer cell types and reported to be a pro-apoptotic transcription factor. The study aimed to observe the ability of two cyclooxygenase-dependent non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of experimentally induced early neoplasm of colon via NF-κB and PPARγ pathways. Early stages of colorectal cancer were produced in rats with 1,2-dimethylhydrazine dihydrochloride. Western blotting and immunohistochemistry were performed along with morphological and histological analysis. According to the expression levels of NF-κB and PPARγ in the cell nuclei, it is observed that NSAIDs may prevent colorectal cancer in the early stages by a concomitant down-regulation of NF-κB and up-regulation of PPARγ. COX-independent mechanism of anti-carcinogenesis was observed by COX-dependent NSAIDs in colorectal cancer.
The effects of Diclofenac and Celecoxib on the expression of pro- and anti-apoptotic proteins have been observed, which may constitute the mechanism by which the NSAIDs are efficient in controlling the proliferation of neoplasm in the colon.
This study explored the role of intrinsic mitochondrial membrane potential (DeltaPsiM) in etoricoxib-mediated apoptosis in 1,2-dimethylhydrazine dihydrochloride (DMH) induced colon cancer. Male Sprague--Dawley rats were divided into four groups: control, DMH, DMH+etoricoxib and etoricoxib. After 6 weeks of treatment period, animals were killed and colons were analyzed for morphological and histopathological features. Well-characterized preneoplastic aberrations such as multiple plaque lesions, hyperplasia and dysplasia were found in the DMH-treated group whereas these features were reduced with coadministration of etoricoxib and DMH. DeltaPsiM was assessed by 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazol carbocyanine iodide (JC-1) fluorescent staining of the isolated colonocytes. DMH treatment led to a significant increase in DeltaPsiM which was found to be low in the DMH+etoricoxib group. The expression of important proapoptotic proteins, cytochrome C and Bax, were analyzed by western blot and immunohistochemistry. DMH treatment reduced the expression of Bax and cytochrome C whereas etoricoxib promoted the expression of the same. Protein expression of antiapoptotic protein Bcl-2 was also studied in colonic mucosa and was found high in the DMH-treated group and low in DMH+etoricoxib treated animals. Etoricoxib treatment may exert its chemopreventive action in colon carcinogenesis by modulating the DeltaPsiM.
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