Abstract
The present study aimed to investigate the anti-cancer mechanism of canagliflozin (CANA) and dapagliflozin (DAPA), sodium-glucose co-transporter-2 (SGLT2) inhibitors, using in silico and in vitro approaches. Network pharmacology was employed to predict the targets of the inhibitors and GO gene enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation conducted to explore the interacting pathways. Molecular docking and molecular dynamic (MD) simulation studies were performed to confirm the important targets and assess conformational stability. In vitro cytotoxicity assays, MIA-PaCa-2 and DU-145 cell lines CANA and DAPA was performed. Protein–protein interaction (PPI) network analysis indicated that CANA and DAPA exert anticancer effects through MAPK, mTOR, EGFR-KRAS-BRAF, FGFR, and PI3KA pathways. KEGG analysis revealed that these inhibitors could be used in the treatment of various cancers, including breast, prostate, pancreatic, chronic myeloid leukemia, thyroid, small cell lung, gastric, and bladder cancer. Docking results showed highest affinity for MAPK1 for CANA (− 9.60 kcal/mol) and DAPA (− 9.58 kcal/mol). MD simulation results showed that RMSD values for the MAPK1-compound exhibit remarkable stability over a timeframe of 100 ns. In cytotoxicity assays using MIA-PaCa-2 and DU-145 cell lines, CANA demonstrated a potential antiproliferative effect on the pancreatic cell line MIA-PaCa-2 after 48 h of treatment at a concentration of 100 µg/ml. Furthermore, CANA arrested the cell cycle in the sub-G1 phase and induced late apoptosis and necrosis in MIA-PaCa-2 cell line. Based on these findings, CANA shows promise as a potential novel treatment strategy for pancreatic cancer.
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The authors are thankful to the Management and Principal of Y. B. Chavan College of Pharmacy, Aurangabad (MS), India, for providing the facilities and infrastructure to carry out the research work.
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The authors of this study, Prasanna Mohite, Deepak Lokwani, and Nikhil S. Sakle, made equal contributions to the research and manuscript preparation. Prasanna Mohite is responsible for designing the experiments and writing the manuscript. Deepak Lokwani conducted the molecular docking and molecular dynamics simulation study, while Nikhil S. Sakle performed the network pharmacology analysis, provided guidance and supervision throughout the research work, and edited the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Mohite, P., Lokwani, D.K. & Sakle, N.S. Exploring the therapeutic potential of SGLT2 inhibitors in cancer treatment: integrating in silico and in vitro investigations. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03021-x
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DOI: https://doi.org/10.1007/s00210-024-03021-x