Combination of cancer preventive Celecoxib derivatives with cell cycle specific drugs enhances therapeutic responses in human oral cancer cell lines.

B84

Combination of compounds targeting specific signaling pathways regulating cell cycle progression and apoptosis may greatly enhance therapeutic responses in cancer prevention. We have shown that treating premalignant and malignant human oral epithelial cell lines with non-COX-inhibitory Celecoxib derivatives delays the progression of cells through the early S phase. We hypothesize that these agents would sensitize cells to S/G2 specific drugs, greatly enhancing the responses to cancer prevention and therapeutic agents. To test this hypothesis, premalignant and malignant human oral cell lines were treated with the Celecoxib derivative, OSU02067, for 12 hr, followed by etoposide, a S/G2 specific drug, for 24hr. Flow cytometry indicated the accumulation of cells in the S phase following OSU02067 treatment. Cytotoxicity assays showed that the combination of these compounds synergistically increased the efficacy over single drug treatments. There was a significantly enhancement in apoptosis as indicated by caspase 3 activation and PARP cleavage. Reversing the combination sequence, i.e., etoposide followed by OSU02067, or adding them together, produced an antagonistic affect. These results suggest that the sequential combinations of celecoxib derivative, synchronizing cells in early S phase of the cell cycle followed by etoposide, targeting late S/G2 can produce synergistic effects on suppressing oral cancer cell growth and inducing apoptosis. This may provide a novel therapeutic strategy in cancer prevention and treatment. Supported by NCI R01-109012.