Repurposing DPP-4 inhibitors as anticancer agents in KRAS-mutated pancreatic ductal adenocarcinoma

  • BMC Pharmacol Toxicol. 2025 Dec 8;26(1):208. doi: 10.1186/s40360-025-01020-z.
Prasanna Srinivasan Ramalingam  #  1 ,  Md Sadique Hussain  #  2 ,  Gayathri Chellasamy  3 ,  Sujatha Elangovan  1 ,  Divya Sharma  1 ,  Premkumar T  4 ,  Rudra Awdhesh Kumar Mishra  5 ,  Gothandam Kodiveri Muthukaliannan  5 ,  Tajamul Hussain  6 ,  Salman Alrokayan  7 ,  Purushothaman Balakrishnan  8 ,  Janaki Ramaiah Mekala  9 ,  Sivakumar Arumugam  10
Affiliations
  • 1. Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, TamilNadu, India.
  • 2. Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, 248007, India.
  • 3. Department of Bionanotechnology, Gachon University, Seongnam-si, Gyeonggi-do, Republic of Korea.
  • 4. Integrative Multiomics Lab, Department of Biotechnology, School of Bio- Sciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
  • 5. High Throughput Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India.
  • 6. Centre of Excellence in Biotechnology Research, King Saud University, Riyadh, 11451, Saudi Arabia.
  • 7. Research Chair for Biomedical Application of Nanomaterials, Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.
  • 8. TanBio R and D Solution, Thiruvarur, TamilNadu, 610103, India.
  • 9. Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India. [email protected].
  • 10. Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, TamilNadu, India. [email protected].
  • # Contributed equally.
PMID: 41361888 DOI: 10.1186/s40360-025-01020-z
Abstract

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.

Keywords
Cancer; DPP-4; Diabetes mellitus; Drug repurposing; Targeted therapy.
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