Epidemiological studies have correlated a decreased risk of pancreatic cancer with patients who take either metformin or aspirin. In addition, animal studies have shown that either metformin or aspirin inhibits pancreatic tumor formation as well as the progression of pancreatic intraepithelial neoplasia (PanIN). Since the combination of metformin and aspirin and their potential synergistic effects on pancreatic cancer cells have not been investigated, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis in pancreatic cancer cell lines PANC-1 and BxPC3. Cell viability and migration were determined using the MTT assay, colony formation, and the wound-healing assay, and the molecular changes in the mTOR and JAK/STAT3 and apoptotic signaling pathways were evaluated. The synergistic effects of the combination of metformin with aspirin were assessed using a method based on isobologram analyses. We observed that the combination of metformin and aspirin at low concentrations showed significant synergistic effects on the inhibition of cell viability, migration and colony formation in both PANC-1 and BxPC-3 cells. We also found that the combination of metformin and aspirin significantly inhibited the phosphorylation of mTOR, S6K, JAK2 and STAT3. Furthermore, the combination of metformin and aspirin significantly inhibited the expression of Bcl-2 and Mcl-1, which are the downstream targets of STAT3, in both mRNA and protein levels. We also observed increased apoptosis as measured by caspase 3 and poly (ADP-ribose) polymerase (PARP) cleavage in PANC-1 cells treated with the combination of metformin and aspirin. These results suggest that metformin and aspirin synergistically induce cell death in pancreatic cancer cells associated with down-regulating Bcl-2 and Mcl-1 through the STAT3 pathway. Our results support the continued investigation of the combination of metformin and aspirin as chemopreventative or therapeutic agents in pancreatic cancer tumor models.

Citation Format: Wen Yue, Yong Lin, Chunxia Chen, Darren R. Carpizo, Robert S. DiPaola, Xiang-Lin Tan. Metformin and aspirin synergistically inhibit mTOR and JAK/STAT3 signaling pathway and induce cell death in pancreatic cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2153. doi:10.1158/1538-7445.AM2014-2153

©2014 American Association for Cancer Research.
2014