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Repurposing DPP-4 inhibitors as anticancer agents in KRAS-mutated pancreatic ductal adenocarcinoma
Prasanna Srinivasan Ramalingam1, Md Sadique Hussain2, Gayathri Chellasamy3
1Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, TamilNadu, India.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Sitagliptin and Linagliptin show promise in fighting KRAS-mutated pancreatic cancer by inhibiting growth and inducing cell death. Repurposing these diabetes drugs offers a new strategy against aggressive pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC), especially KRAS-mutated types, presents a significant therapeutic challenge due to its aggressiveness and limited treatment options.
- Drug repurposing offers a cost-effective strategy with established safety profiles for developing novel cancer therapies.
- Dipeptidyl Peptidase-4 (DPP-4) inhibitors, Sitagliptin and Linagliptin, used for Type 2 Diabetes Mellitus (T2DM), have shown potential in inducing cancer cell death.
Purpose of the Study:
- To investigate the therapeutic potential of Sitagliptin and Linagliptin in KRAS-mutated PDAC.
- To evaluate the effects of DPP-4 inhibitors on cancer cell proliferation, migration, and apoptosis.
- To explore the underlying molecular mechanisms, including gene expression and pathway enrichment, of DPP-4 inhibitors in PDAC.
Main Methods:
- Assessed proliferation, wound healing, and colony formation in KRAS G12C (MIA PaCa-2) and KRAS G12D (PANC-1) mutated PDAC cells.
- Measured reactive oxygen species (ROS) induction, DNA fragmentation, and apoptosis using flow cytometry.
- Utilized network pharmacology, Gene Ontology (GO), and KEGG pathway analysis to identify key molecular targets and pathways.
Main Results:
- Sitagliptin and Linagliptin significantly inhibited PDAC cell proliferation, migration, and colony formation.
- Both drugs increased intracellular ROS levels, induced DNA fragmentation, and promoted apoptosis.
- Gene expression analysis revealed regulation of MAPK and apoptosis-related pathways, supported by network pharmacology findings.
Conclusions:
- Sitagliptin and Linagliptin demonstrate significant anticancer potential against KRAS-mutated PDAC.
- Repurposing DPP-4 inhibitors presents a viable therapeutic strategy for aggressive pancreatic cancers.
- Further investigation into drug repurposing is recommended to overcome clinical resistance in PDAC.
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