Bcl-2 family of proteins is implicated in the malignant tumors including colorectal cancer. Activation of Bcl-2 inhibits the pro-apoptotic proteins (Bax and Bad) and regulates many biological processes such as apoptosis, cell proliferation and cell growth. As the mitochondrial enzymes are involved in sphingolipid metabolism, it can regulate ceramide formation and in turn mitochondria play a central role for the regulation of ceramide induced apoptosis. Bcl-2/ BclxL activates sphingosine kinases (SKs), resulting in the accumulation of S1P (sphingosine-1-phosphate), thereby reducing apoptosis. In the present study, the anti-neoplastic effects have been observed of Etoricoxib and Celecoxib, two COX-2 selective non-steroidal anti-inflammatory drugs (NSAIDs), and Diclofenac, a preferential COX-2 inhibitory NSAIDs, in the early stage of colon cancer in rats. These NSAIDs regress the expressions of Bcl-2 and SK-1 and promote apoptosis. Gross morphological analysis revealed the occurrence of raised mucosal lesions called MPL or multiple plaque lesions, which were maximum in the 1, 2-Dimethylhydrazine (DMH) treated group and their number regressed with the co-administration of the NSAIDs. An abnormal histo-architecture like hyperplasia and dysplasia were evident in the carcinogenic group, which were reduced with NSAIDs co-administration.