Combined treatment of gemcitabine with indole-3-carbinol or metformin on drug efficacy in pancreatic cancer cell lines: The role of human equilibrative nucleoside transporters

Pancreatic cancer is one of the most lethal carcinomas in the United States. In accord with the American Cancer Society pancreatic cancer is anticipated to move from the third to the second leading cause of deaths in the United States by 2020. Although the standard treatment for advanced pancreatic cancer is gemcitabine (GEM), the response rate is less than 20%. Chemoresistance is a hallmark of this cancer, and modulation of drug transporters expression has been shown to increase cancer drug efficacy. Studies have shown that human equilibrative nucleoside transporters (hENTs) expression patterns may predict GEM treatment efficacy. This study investigated whether or not GEM in combination with metformin (MET) or indole-3-carbinol (I3C) increases cytotoxicity and modulates hENT1 and hENT4. Pancreatic cancer cells from males and females were treated for 24 or 72h with GEM and/or MET or I3C. Cell viability, drug interactions, and protein and mRNA expression levels of hENTs were assessed. Treatment with GEM and/or MET or I3C showed cell line specific reductions in pancreatic cancer cell proliferation, and modulation of hENT1 and hENT4 expression. Response to GEM and MET/I3C may be dependent upon the genetic profile of the tumor and the level of expression of a specific transporter. The sensitivity of GEM could depend on the method of treatment, whether cells were pre-treated with MET or I3C, which studies, including our own, have showed that pre-treatment with I3C increased upregulation of hENT1 expression in pancreatic cancer cell lines.