COX-2 independent induction of apoptosis by two synthetic COX-2 inhibitors in breast cancer cell line

Background: Breast cancer is considered to be the most familiar malignant tumor in females in western countries; and is becoming more and more widespread in Asia. Apoptosis is an intricate molecular program with favorable application in many tumor treatments. Cyclooxygenase (COX)-2 inhibitors may induce apoptosis through the COX-2-independent mechanism via a mitochondrial pathway. In view of the reported antiproliferative activities of compounds 1 (3-(4-chlorophenyl)-5-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1,2,4- oxadiazole) and 2 (3,5-bis(4-chlorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole) as two COX-2 inhibitor derivatives in breast cancer cells (MCF-7), the present study was undertaken to evaluate the potential of these compounds to induce apoptosis and unravel the associated mechanisms.

Material and Methods: The apoptotic activities of compounds 1 and 2 were assessed using flowcytometry. Protein expression was determined by western blot analysis and immunoassay kit.

Results: Compounds 1 and 2 induced MCF-7 cells to undergo apoptosis, which was demonstrated by annexin-V and propidium iodide staining. Further investigation showed that compounds 1 and 2 inhibited nuclear factor kappalight-chain-enhancer of activated B cells (NF-úB), ferritin heavy chain (FHC) and extra cellular signal-regulated kinase (ERK) activation, whereas it could not change COX-2, c-Myc and early growth response protein 1 (EGR-1) expression dramatically.

Conclusion: Altogether, these results revealed that compounds 1 and 2 may be potential and promising chemotherapeutic agents to treat breast cancer through COX-2-independent and NF-úB-dependent pathways, which sequentially inhibit P-ERK and FHC expressions.