Anticancer potential of combined antidiabetic drugs in pancreatic cancer treatment

Despite significant advances in the understanding, prevention, diagnosis and treatment of pancreatic cancer, it continues to affect millions of people around the world. People with diabetes have an increased lifetime risk of developing pancreatic cancer. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and metformin are drugs widely used to treat type 2 diabetes, and both have been associated with a reduction in the risk of pancreatic cancer.

A recent study conducted by researchers from the Faculty of Medicine and the Faculty of Pharmacy at the University of Porto, led by researcher Fátima Martel, showed that the combination of SGLT2 inhibitors with metformin seems to increase their anti-cancer effects in pancreatic cancer cell lines (PANC-1 and AsPC-1). Indeed, the study showed that the combination of canagliflozin or dapagliflozin with metformin results in increased cytotoxic, antimigratory, proapoptotic and G1 cell cycle arrest effects, with specific effects for each type of cell line. In addition, the study showed that the cytotoxic effect of SGLT2 inhibitors on AsPC-1 cells depends on the PI3K and JNK signaling pathways, whereas metformin appears to exert its effect through a different mechanism.

The results suggest new therapeutic approaches and highlight the potential for drug repurposing as an effective strategy in the treatment of pancreatic cancer.

Authors and Affiliations:

André Cristovão¹, Nelson Andrade^1,2, Fátima Martel^1,3 and Cláudia Silva^1,2

¹ Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal;

² LAQV/ REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4200-135 Porto, Portugal

³ Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal

Abstract:

Pancreatic cancer (PC) is the ninth-leading cause of cancer-related deaths worldwide. Diabetic patients have an increased risk and mortality rates for PC. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and metformin (Met) are widely used anti-diabetic medications. Both Met and SGLT2 inhibitors have anticancer properties in PC, but nothing is known concerning their combined effect. So, we investigated the in vitro effect of SGLT2 inhibitors combined with Met. Canagliflozin and dapagliflozin possessed cytotoxic, antiproliferative, and pro-apoptotic properties in the tested cell lines. In PANC-1 cells, the antimigratory and pro-apoptotic effects were enhanced when dapagliflozin was combined with Met, and G1 cell cycle arrest was enhanced when dapagliflozin or canagliflozin was combined with Met. In AsPC-1 cells, the cytotoxic effect and the G1 cell cycle arrest were enhanced when canagliflozin and dapagliflozin, respectively, were combined with Met. Only the cytotoxic effects of SGLT2 inhibitors, but not the combination treatments, involved PI3K and JNK-dependent pathways in AsPC-1 cells. In conclusion, combination treatments increased the anticancer effects in a cell type-dependent way in the two investigated cell lines. Additionally, the cytotoxic effect of SGLT2 inhibitors was dependent on the PI3K and JNK pathways in AsPC-1 cells, but Met appears to act via a distinct mechanism.

Journal: International Journal of Molecular Sciences

Link: https://doi.org/10.3390/ijms25189932