biostudies-literatureUnknown26(1)Ramalingam PS<h4>Background</h4>Cancer has become a global health threat with increasing incidence & mortality rates, and despite significant advancements in diagnostics and therapeutics, they limited for aggressive cancers like pancreatic ductal adenocarcinoma (PDAC). To note, KRAS-mutated PDAC is very frequent and limited by potent therapeutics due to their aggressiveness. Drug repurposing has become a potent strategy due to cost-effective, established safety & toxicity profiles. Sitagliptin and Linagliptin are Dipeptidyl Peptidase-4 (DPP-4) inhibitors, which are being used to manage Type 2 Diabetes Mellitus (T2DM). Recent studies have indicated that they have the potential to induce apoptotic-mediated cell death in cancer.<h4>Methods</h4>In the current study, we examined the therapeutic potential of these DPP-4 inhibitors in proliferation, wound healing, and colony formation, ROS induction, DNA fragmentation, apoptosis induction, and regulation of gene expression in KRAS G12C-mutated MIA PaCa-2 & KRAS G12D-mutated PANC-1 PDAC cells. Additionally, the network pharmacology, Gene Ontology (GO) & KEGG pathways enrichment were also studied for DPP-4 inhibitors in PDAC.<h4>Results</h4>The results indicated that both drugs inhibited the proliferation, migration, & colony formation; elevated intracellular ROS levels; induced DNA fragmentation, regulated MAPK & apoptosis-related gene expression, and induced apoptosis confirmed by flow cytometry. In addition, the network pharmacology analysis supported that the identified hub genes plays a role in apoptosis.<h4>Conclusions</h4>Overall, we report that Sitagliptin and Linagliptin have significant anticancer potential towards KRAS-mutated PDAC. Furthermore, we recommend repurposing of more drugs to examine their anti-cancer potential towards these aggressive cancers and to overcome clinical resistance in the near future.BMC pharmacology & toxicology208https://www.ebi.ac.uk/biostudies/studies/S-EPMC12687489biostudies-literatureRepurposing DPP-4 inhibitors as anticancer agents in KRAS-mutated pancreatic ductal adenocarcinoma.PMC12687489Chellasamy GT PKodiveri Muthukaliannan GArumugam SMekala JRHussain MSRamalingam PSSharma DHussain TMishra RAKAlrokayan SBalakrishnan PElangovan SfalseRepurposing DPP-4 inhibitors as anticancer agents in KRAS-mutated pancreatic ductal adenocarcinoma.<h4>Background</h4>Cancer has become a global health threat with increasing incidence & mortality rates, and despite significant advancements in diagnostics and therapeutics, they limited for aggressive cancers like pancreatic ductal adenocarcinoma (PDAC). To note, KRAS-mutated PDAC is very frequent and limited by potent therapeutics due to their aggressiveness. Drug repurposing has become a potent strategy due to cost-effective, established safety & toxicity profiles. Sitagliptin and Linagliptin are Dipeptidyl Peptidase-4 (DPP-4) inhibitors, which are being used to manage Type 2 Diabetes Mellitus (T2DM). Recent studies have indicated that they have the potential to induce apoptotic-mediated cell death in cancer.<h4>Methods</h4>In the current study, we examined the therapeutic potential of these DPP-4 inhibitors in proliferation, wound healing, and colony formation, ROS induction, DNA fragmentation, apoptosis induction, and regulation of gene expression in KRAS G12C-mutated MIA PaCa-2 & KRAS G12D-mutated PANC-1 PDAC cells. Additionally, the network pharmacology, Gene Ontology (GO) & KEGG pathways enrichment were also studied for DPP-4 inhibitors in PDAC.<h4>Results</h4>The results indicated that both drugs inhibited the proliferation, migration, & colony formation; elevated intracellular ROS levels; induced DNA fragmentation, regulated MAPK & apoptosis-related gene expression, and induced apoptosis confirmed by flow cytometry. In addition, the network pharmacology analysis supported that the identified hub genes plays a role in apoptosis.<h4>Conclusions</h4>Overall, we report that Sitagliptin and Linagliptin have significant anticancer potential towards KRAS-mutated PDAC. Furthermore, we recommend repurposing of more drugs to examine their anti-cancer potential towards these aggressive cancers and to overcome clinical resistance in the near future.2025-01-01T00:00:00Z2025 Dec2026-05-23T03:23:16.536Z2026-05-23T03:13:55.508ZS-EPMC126874894136188810.1186/s40360-025-01020-z