Malignant transformation and antineoplastic actions of nonsteroidal antiinflammatory drugs (NSAIDs) on cyclooxygenase-null embryo fibroblasts

In this study, we use primary embryonic fibroblasts derived from cyclooxyge nase-deficient transgenic embryos to further investigate the role of the tw o cyclooxygenases, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), i n the process of neoplastic transformation. Cells with either, neither, or both of the cyclooxygenases were transformed by Ha-ras and/or SV40. Our res ults show that when a cyclooxygenase enzyme is present, the transformed cel ls have marked increases in COX-2 and/or COX-1 expression. Nevertheless, ea ch type of cell, deficient in either or both cyclooxygenases, can be readil y transformed at almost equal efficiency. Different nonsteroidal antiinflam matory drugs (NSAIDs) were used to examine their possible antineoplastic ef fects on the transformed cells, which have various levels of expression of COX-1 or COX-2. Our results show that NSAIDs suppress the colony formation in soft agar in a dosage-dependent manner in the absence of the cyclooxygen ase(s). Thymidine incorporation and apoptosis analyses further demonstrate that the NSAIDs are effective in the cyclooxygenase-null cells. Our finding s with cyclooxygenase knockout cells confirm recent reports that some of th e antiproliferative and antineoplastic effects of NSAIDs are independent of the inhibition of either COX-1 or COX-2. They also show that transformatio n is independent of the status of cyclooxygenase expression, suggesting tha t the involvement of the cyclooxygenases in tumorigenesis may occur at late r steps.