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Effect of dapagliflozin on colon cancer cell [Rapid Communication]
Tsugumichi Saito1, Shuichi Okada, Eijiro Yamada
1Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan.
Abstract:
Dapagliflozin is a SGLT2 (Sodium/Glucose cotransporter 2) inhibitor that reduces circulating glucose levels in type 2 diabetic patients by blocking the SGLT2-dependent reabsorption of glucose in the kidney. Dapagliflozin is metabolized by UGT1A9 (UDP Glucuronosyltransferase 1 family, Polypeptidase A9), suppressing its SGLT2 inhibitor activity. However little information is available on whether dapagliflozin acts in the absence of dapagliflozin metabolism. Treatment with 0.5μM dapagliflozin significantly reduced the number of HCT116 cells, which express SGLT2 but not UGT1A9. This was independent of SGLT2 inhibition, as the SGLT2 inhibitor phlorizin had no effect. Dapagliflozin also enhanced Erk phosphorylation but without changing levels of uncleaved and cleaved PPAR and uncleaved caspase-3, suggesting that the cause of the decrease in HCT116 cell number was apoptosis independent cell death. Taken together, these data indicate a new potential role for dapagliflozin as an anticancer reagent in tumor cell populations that do not express UGT1A9.
Insights
Dapagliflozin shows anticancer potential in cells lacking UGT1A9 metabolism. This Sodium/Glucose cotransporter 2 inhibitor reduced cancer cell numbers independently of its glucose-lowering effects.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Dapagliflozin is a Sodium/Glucose cotransporter 2 (SGLT2) inhibitor used for type 2 diabetes.
- It is metabolized by UDP Glucuronosyltransferase 1 family, Polypeptidase A9 (UGT1A9), which can suppress its activity.
- The action of dapagliflozin independent of its metabolism is not well understood.
Purpose of the Study:
- To investigate the effects of dapagliflozin on cancer cells that do not express UGT1A9.
- To determine if dapagliflozin exhibits anticancer activity independent of SGLT2 inhibition and UGT1A9 metabolism.
Main Methods:
- Treatment of HCT116 cells (expressing SGLT2 but not UGT1A9) with dapagliflozin.
- Assessment of cell number, Erk phosphorylation, and levels of PPAR and caspase-3.
- Comparison with the SGLT2 inhibitor phlorizin.
Main Results:
- Dapagliflozin significantly reduced HCT116 cell number, independent of SGLT2 inhibition.
- Erk phosphorylation was enhanced, but apoptosis-related proteins remained unchanged, suggesting apoptosis-independent cell death.
- Phlorizin, an SGLT2 inhibitor, had no effect on cell number.
Conclusions:
- Dapagliflozin demonstrates potential as an anticancer agent in tumor cells lacking UGT1A9.
- Its mechanism involves apoptosis-independent cell death, distinct from its SGLT2 inhibitory action.
