Roflumilast enhances cisplatin-sensitivity and reverses cisplatin-resistance of ovarian cancer cells via cAMP/PKA/CREB-FtMt signalling axis.

OBJECTIVE:We previously demonstrated the roflumilast inhibited cell proliferation and increased cell apoptosis in ovarian cancer. In this study, we aimed to investigate the roles of roflumilast in development of cisplatin (DDP)-sensitive and -resistant ovarian cancer. METHODS:OVCAR3 and SKOV3 were selected and the corresponding DDP-resistant cells were constructed. Cell viability, proliferation, apoptosis, cycle were performed. Expression cAMP, CREB, phosphorylation of CREB and FtMt were detected. The roles of roflumilast in development of DDP-sensitive and -resistant ovarian cancer were confirmed by xenograft model. RESULTS:Roflumilast + DDP inhibited cell proliferation, and induced cell apoptosis and G0/G1 arrest in OVCAR3 and SKOV3 cells, roflumilast induced expression of FtMt, the activity of cAMP and and phosphorylation of CREB in ovarian cancer cells and the above-effect were inhibited by H89. Downregulation of CREB inhibited the roflumilast-increased DDP sensitivity of ovarian cancer cells, and the roflumilast-induced FtMt expression and phosphorylation of CREB. Also, roflumilast reversed cisplatin-resistance, and induced expression of FtMt and activation of in DDP-resistant ovarian cancer cells. Similarly, treated with H89 or downregulation of CREB inhibited the changes induced by roflumilast. In vivo, roflumilast inhibited the development of SKOV3 or SKOV3-DDP-R xenograft models. CONCLUSIONS:Roflumilast enhanced DDP sensitivity and reversed the DDP resistance of ovarian cancer cells via activation of cAMP/duanyu1529/CREB pathway and upregulation of the downstream FtMt expression, which has great promise in clinical treatment.

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