Identification of epigenetic modulators that synergize with triptolide or the triple combination of gemcitabine, nab-paclitaxel, and cisplatin in pancreatic cancer cells
The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC) which is extremely lethal with a five-year survival rate of less than 7%. PDAC is often detected at a late stage with only 20% of patients eligible for surgical resection at the time of diagnosis, while the majority of patients rely on chemotherapies, which have a modest effect with substantial toxicity. Clearly, new therapeutic agents are necessary to improve patients’ survival rate. The goal of this study is to identify epigenetic modulators that can sensitize pancreatic cancer cells to the treatment of triptolide, a super-enhancer interactive agent or the triple combination of gemcitabine, nab-paclitaxel, and cisplatin. To achieve this goal, pancreatic cancer cells (MIA PaCa-2) were cultured and seeded in 96-well plate. After an overnight incubation, pancreatic cancer cells were dosed with drugs consisting of fixed concentrations of 86 epigenetic drugs and IC50 of triptolide or the triple combination. After 72 hours of incubation, the plates were processed using Sulforhodamine B (SRB) method which measures cell proliferation based on the amount of proteins within each plate well. The percentage of cell survival compared to vehicle control in each well was then calculated to determine whether or not the combination treatment showed synergistic effect. From this, several epigenetic modulators were identified to show synergism with triptolide or the triple combination. Those positive hits are currently being verified with additional drug doses and cell lines. If validated, those combinations can be further developed for the treatment of patients with pancreatic cancer to improve their survival.