Sodium-glucose cotransporter type 2 inhibitors prevent ponatinib-induced endothelial senescence and disfunction: A potential rescue strategy

Background: Ponatinib (PON), a third-generation tyrosine kinase inhibitor (TKI), has proven cardiovascular toxicity, with no known preventing agents usable to limit such side effect. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a new class of glucose-lowering agents, featuring favorable cardiac and vascular effects. Aims: We assessed the effects of the SGLT2 inhibitors empagliflozin (EMPA) and dapagliflozin (DAPA) on human aortic endothelial cells (HAECs) and underlying vasculo-protective mechanisms in an in vitro model of PON-induced endothelial toxicity. Methods and results: We exposed HAECs to PON or vehicle (DMSO) in the presence or absence of EMPA (100 and 500 nmol/L) or dapagliflozin (DAPA) for 0-48 h exposure times. Compared with vehicle, incubations of HAECs with PON significantly reduced cell viability (0.56 +/- 0.11 vs 0.23 +/- 0.05 absorbance units, p < 0.01), increased the number of senescent cells at beta-gal-assay (PON 9 +/- 4 vs basal DMSO 3 +/- 1 beta-Gal(+) cells/field, p < 0.01), decreased tubulization in Matrigel (PON PON: 6 +/- 1 vs basal DMSO 12 +/- 1 tubuli number/field, p < 0.05) with a non-statistically significant trend of PON to decrease the number of autophagic cells at immunofluorescence assay and flow cytometry. EMPA reverted the effects of PON on cell viability (E 500 + PON 0.24 +/- 0.05 vs PON 0.56 +/- 0.11 absorbance units, p < 0.01) and induced autophagy (E 500 7 +/- 4.3 vs basal DMSO 2.6 +/- 2.3 mean fluorescence vs PON 2.6 +/- 2.4 mean fluorescence, p < 0.05). EMPA and DAPA also reversed the effects of PON on cell senescence (E 500 + PON 4 +/- 1 and DAPA 100 4 +/- 2 vs PON 9 +/- 4 beta-Gal(+) cells/field, p < 0.01) and improved cell tubulization (E 500 + PON 21 +/- 3 vs PON 6 +/- 1 tubuli number/field, p < 0.05; DAPA 100 + PON 16 +/- 2 vs PON 6 +/- 1 tubuli number/field, p < 0.05). Conclusion: EMPA and DAPA attenuate the vasculo-toxic effect exerted by PON by reverting endothelial cell senescence and dysfunction. These findings support the design of clinical studies exploring the vasculo-protective effects of EMPA or DAPA on PON-induced vascular toxicity.

Automated summary

This study investigated the effects of SGLT2 inhibitors on PON-induced endothelial cell toxicity. The results showed that EMPA and DAPA could reverse the effects of PON on cell viability, cell senescence, and cell tubulization, thereby attenuating PON-induced vascular toxicity.