Mechanistic study of DAC synergizing with cabergoline in the treatment of drug-resistant prolactinomas

Pituitary prolactin adenomas are the most common functional pituitary adenomas and are preferred to be treated with dopamine agonists. However, about 20%-40% of prolactin adenomas are clinically resistant to dopamine agonists and are poorly treated with surgery and radiotherapy; therefore, further studies are needed to improve the sensitivity of prolactinomas to dopamine agonists. The results of our previous study confirmed that the drug-resistant behavior of prolactin adenomas is associated with decreased expression of dopamine D2 receptor (D2R) in tumor tissues as well as Wnt pathway inhibitors WIF-1 and SFRP4, which are associated with DNA promoter hypermethylation. It was also demonstrated that the DNA methylation transferase inhibitor decitabine (DAC) induced demethylation of the WIF-1 promoter in GH3 cells to up-regulate gene expression and inhibited the proliferative activity of GH3 cells. Therefore, the present study was designed to combine DAC and the dopamine agonist cabergoline in in vivo and ex vivo experiments to elucidate the sensitivity of DAC to dopamine agonists in drug-resistant prolactin adenomas, and to further elucidate the possible mechanisms of the Wnt pathway and the D2R pathway in this effect, so as to lay a research foundation for the clinical treatment of drug-resistant prolactinomas in the later stage of the disease.