Evidence continues to mount that celecoxib and its derivatives may be “versatile” anticancer agents targeting multiple COX-dependent and -independent pathways to arrest progression and induce cell death in a number of cancers.
Celecoxib and other COX-2 specific NSAIDs have shown promising anticancer activity in different tumor types, Dr. Steven M. D’Ambrosio from Ohio State University in Columbus explained in a telephone interview with Reuters Health. Because COX-2 is often overexpressed in cancer cells, these agents are thought to interfere with the growth of cancer cells largely via COX-2-dependent pathways. However, recent studies with celecoxib suggest that its apoptotic properties may also be mediated through COX-independent pathways. To better understand the COX-independent anticancer mechanisms of these agents, Dr. D’Ambrosio and colleagues studied the effects of celecoxib and second-generation celecoxib derivatives lacking COX-2 inhibitory activity in cultured premalignant and malignant oral epithelial cells. They report in the February 20th International Journal of Cancer that cells exposed to celecoxib and its derivatives “delayed the progression of cells through the G2/M phase of the cell cycle and induced apoptosis.” These derivatives, designed by co-author Dr. Ching-Shih Chen at the School of Pharmacy at Ohio State, also induced cell death with a 2- to 4-fold greater potency than celecoxib. “This shows that we can take a very effective molecule that is used for one thing and modify it to make it even more effective against cancer and at lower doses,” Dr. D’Ambrosio told Reuters Health. Unlike previous studies with prostate cancer cell lines, the P13K/ Akt signaling pathway did not appear to be a critical target for cell cycle arrest or apoptosis in the oral cell lines. Instead, celecoxib derivative-induced apoptosis in oral cells seems to occur via disruption of mitochondria leading to activation of caspase 9 and downstream caspase 3 and 8, independent of Bcl-2, the investigators report. This is also true for lymphoma cell lines. The current studies, together with prior studies, suggest that celecoxib and its derivatives target a variety of signaling pathways that regulate cell death and “could potentially deliver multifaceted anticancer effects to a variety of tumor cell types,” the researchers suggest in their report. (Source: Int J Cancer 2005;113:803-810: Reuters Health: Megan Rauscher: Oncolink: February 2005.)