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Combining Mass Spectrometry Analytical Workflows and Automated Image Analysis to Uncover the Spatial Heterogeneity of Tumor-Associated Glycan Networks in Gastric Cancer
No full textEffect of SGLT2 Inhibitors on pancreatic cancer initiation and progression
No full textPancreatic cancer is a highly aggressive disease and the ninth leading cause of cancer-related deaths worldwide. Epidemiological evidence shows that diabetic patients have an increased cancer risk and a higher mortality rate.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are widely used in the treatment of type 2 diabetes. Because of their favorable effects on cardiovascular risk and renal disease progression, they are considered to be among the first-choice drugs in the case of metformin failure. Metformin has been in use for over half a century and is the world most widely prescribed anti-diabetic medication.
Previous evidences suggest that SGLT2 inhibitors may affect cancer risk, although a meta-analysis of the randomized controlled trial results is inconclusive. Interestingly, SGLT2 is overexpressed in various cancers, including pancreatic cancer, and SGLT2 inhibitors were recently shown to have antitumorigenic properties in this cancer type. Importantly, dual therapy using metformin and SGLT2 inhibitors is superior for type 2 diabetes treatment, when compared with monotherapy, but nothing is known concerning the effect of this combination on pancreatic cancer initiation and progression. This is especially important as metformin has been associated with a reduced risk of pancreatic cancer (preventive effect) or improved survival of patients with pancreatic cancer (therapeutic effect).
So, this work aims to investigate the effect of SGLT2 inhibitors on in vitro pancreatic cancer progression, alone and in combination with metformin.
Two pancreatic cancer cell lines (PANC-1 and AsPC-1) and a normal fibroblast cell line (HDFa) were used. The effects of canagliflozin and dapagliflozin and/or metformin on cell proliferation (3H-thymidine incorporation assay), viability (MTT assay), glucose uptake (3H-deoxy-D-glucose uptake assay), cell migration (injury assay), apoptosis (annexin-V) and cell cycle (flow cytometry) were evaluated.
SGLT2 inhibitors were found to be cytotoxic and antiproliferative for the pancreatic tumor cell lines tested and to increase the number of cells undergoing apoptosis. The antimigratory effect, the effect on the cell cycle (G1 phase arrest) and the pro-apoptotic effect were enhanced when the SGLT2 inhibitor was combined with metformin. We also verified that the cytotoxic effects of Dap and Can in AsPC-1 cells involves PI3K and JNK-dependent pathways. In contrast, the cytotoxic effects of Can+Met and Dap+ Met were not sensitive to PI3K or JNK inhibition.
In conclusion, combination of an SGLT2 inhibitor with Met was able to increase some of the in vitro antitumoral effects of the compounds (namely, the antimigratory and cell cycle arrest), in two distinct pancreatic cancer cell lines. Moreover, the cytotoxic effect of Dap and Can in AsPC-1 cells is dependent on PI3K and JNK pathways, but the cytotoxic effect of their combination is independent of these intracellular signaling pathways
