Growth Inhibition or Apoptosis after Treatment with Motexafin Gadolinium and Celecoxib Is Cell Line Dependent and Correlates with p27 Levels.

Motexafin gadolinium (MGd, Xcytrin^®) is a tumor selective expanded porphyrin belonging to the class of compounds known as texaphyrins. MGd is a redox mediator that may be directly cytotoxic or growth inhibitory to various tumor cells and can potentiate the effects of chemotherapeutic agents and radiation therapy. Initial promising activity has been seen in an ongoing phase II study of MGd as a single agent in patients with lymphoma. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to induce apoptosis and growth inhibition and potentiate the effects of chemotherapeutic agents. To determine potential synergistic effects of MGd and celecoxib, we treated lymphoma cell lines HF-1, Ramos, DHL-4 and Raji with MGd, celecoxib or the combination. Apoptosis was a prominent feature in two of the cell lines (HF-1 and Ramos) treated with MGd/celecoxib, whereas, growth inhibition was more prominent in the other two (DHL-4 and Raji). In Ramos cells, MGd/celecoxib treatment was synergistic in inducing apoptosis and resulted in activation of a caspase cascade as demonstrated by cleavage of caspases-9, -8, -3 and cleavage of substrates Bid and PARP. Two other specific COX-2 inhibitors, rofecoxib and valdecoxib did not synergize with MGd to induce apoptosis in Ramos cells, suggesting that celecoxib potentiation of MGd is a COX-2-independent activity of celecoxib. MGd/celecoxib-induced apoptosis of HF-1 and Ramos correlated with a decrease in p27Kip1 levels whereas MGd/celecoxib-induced growth inhibition of DHL-4 and Raji correlated with increased p27Kip1 levels. Cell cycle profiles of MGd/celecoxib treated Ramos and Raji cells revealed G1 accumulation only in Raji cells, consistent with elevated levels of active p27Kip1. Our pre-clinical data suggest that celecoxib enhances the efficacy of MGd and indicates a role for p27 in the response of cells to MGd and celecoxib.