Celecoxib enhances the response of tumor cells to cisplatin through upregulating PUMA in non–small cell lung cancer carrying wild-type p53

Abstract

Abstract Celecoxib, a cyclooxygenase-2 inhibitor, can enhance the efficacy of chemotherapy; however, its effect seems inconsistent. In this study, we investigated whether celecoxib would increase the antiproliferative effects of cisplatin in human lung cancer cells. Our data demonstrated the synergistic effects of celecoxib with cisplatin in wild-type p53 cells and their antagonistic effects in mutated or deleted p53 cells. Combination indices of 0.82 to 0.93 reflected a synergistic effect between celecoxib and cisplatin in lung cancer cells with wild-type p53. Combination indices of 1.63 to 3.00 reflected antagonism between celecoxib and cisplatin in lung cancer cells with mutated or deleted p53. Compared with that in cells with mutated or deleted p53, apoptosis significantly increased with the addition of celecoxib and cisplatin in wild-type p53 cells (P < 0.05). Moreover, the results in vivo were similar to those in vitro: celecoxib combined with cisplatin slowed tumor growth in wild-type p53 groups and not in mutated or deleted p53 groups. In addition, celecoxib promoted p53 translocation into the nucleus and upregulated active p53 expression in wild-type p53 cells. Celecoxib combined with cisplatin upregulated PUMA (PUMA is a downstream gene of p53) after active p53 increased in wild-type p53 cells. In summary, the combination of celecoxib and cisplatin demonstrates clear synergistic effects in wild-type p53 cells and antagonistic effects in mutated or deleted p53 cells. The synergistic effect was achieved by apoptosis, induced by upregulating PUMA. Our results will provide a new treatment strategy for patients carrying wild-type p53, insensitive to cisplatin.