Table 3.
In Vitro Studies Demonstrating the Cardioprotective Effects of SGLT2 Inhibitors Against Cancer Treatment–Related Cardiotoxicity
| First Author (Year) | Cell Type | Anticancer Treatment | SGLT2 Inhibitor Treatment | Key Findings | Results and Proposed Mechanisms |
|---|---|---|---|---|---|
| Wang et al (2020)41 | Isolated neonatal rat ventricular cardiomyocytes and AC16 human cardiomyocytes | DOX (1 μM for 24 h) | EMPA (200 nM) | EMPA protected cells from DOX-induced apoptosis | ↑ Autophagic flux (↑ the LC3-II/LC3-I ratio) ↑ Binding of SIRT3 to the beclin 1-TLR9 complex through TLR9 ↓ ROS levels and DNA damage |
| Quagliariello et al (2021)43 | HL-1 adult mouse cardiomyocytes | DOX (0.1-50 μM for 24 h) DOX (100 nM for 12 h) |
EMPA (10, 50, 100, and 500 nM) | ↑ Viability ↓ Apoptosis |
↓ [Ca2+]i ↓ iROS, MDA 4-HNA, NO ↓ IL-8, IL-6, IL1-β ↓ Leukotrienes B4 ↓ p65/NF-κB ↓ MyD88 and NLRP3 |
| Lin et al (2023)82 | Isolated ventricular myocytes | DOX (1 μM for 120 min) | EMPA (1 μM 30 min before DOX) | ↓ Contraction malfunction | ↓ Mitochondrial ROS production ↓ Ca2+-handling disorders by ↑ Ca2+ transients, ↓ Ca2+ transient decay time, ↓ frequency of Ca2+ sparks, and ↑ Ca2+ content in the sarcoplasmic reticulum ↓ Oxidation of Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) and CaMKII-dependent phosphorylation of RyR2 |
| Chang et al (2021)44 | H9c2 rat cardiac myoblast | DOX (1 μM for 24 h) with high glucose | DAPA (10 μM 1 h before DOX) | ↓ Apoptosis | ↓ ROS generation ↓ ER stress |
| Chang et al (2022)46 | H9c2 rat cardiac myoblast | DOX (1 μM for 24 h) | DAPA (10 μM 1 h before DOX) | ↓ Apoptosis | ↓ ROS ↑ STAT3 expression |
| Hsieh et al (2022)47 | H9c2 rat cardiac myoblast | DOX (10 μM for 24 h) | DAPA (0-20 μM) | ↓ Apoptosis ↑ Viability |
↑ AKT/PI3K signaling ↑ Nrf2 nuclear translocation and activation ↑ Antioxidant HO-1, NQO1, and SOD activity ↓ Oxidative stress and mitochondrial dysfunction ↓ Smad3 activation ↓ ANP, BNP, collagen I, fibronectin, and α-SMA ↓ Fibrosis, inflammation ↓ p38 activation, nuclear NF-κB p65, IL-8 |
| Hu et al (2023)50 | H9c2 rat cardiac myoblast | DOX (5 μM for 24 h) | DAPA (5 μM) | ↓ NLRP3 inflammasome ↓ Inflammatory markers (IL-6, IL-1β, and TNF-α) ↓ Phosphorylated p38, phosphorylated ERK, and TLR4 |
|
| Quagliariello et al (2020)55 | AC16 human cardiomyocytes | Ipilimumab (50-500 nM for 72 h) for cell viability, then 100 nM for 12 h | EMPA (500 nM) | EMPA under hyperglycemic conditions ↓ cardiotoxicity of ipilimumab with ↑ responsiveness to ipilimumab in breast cancer cell lines | ↓ Leukotrienes type B4 production ↓ ROS production, MDA ↓ p65-NF-κB expression ↓ NLRP3 and MyD88 ↓ Cytokines and growth factors (IL-1β, IL-6, PDGF, VEGF, TGF-β) |
| Maurea et al (2021)54 | Coculture model of hPBMCs and cardiomyocytes | Ipilimumab (200 nM for 72 h) | DAPA | ↑ Viability | ↓ [Ca2+]i ↓ Lipid peroxidation ↓ p65/NF-κB ↓ IL-8, IL-6, IL1-β ↓ NLRP3 inflammasome |
| Ren et al (2021)20 | H9c2 rat cardiac myoblast | Sunitinib (1-20 μM for 48 h) | EMPA (50-1,000 nM for 48 h) | ↑ Viability | Autophagy restoration Restored the AMPK/mTOR signaling pathway Inhibition of AMPK or autophagy abolished EMPA effects |
| Madonna et al (2022)56 | HAECs | Ponatinib (1.7 nM) for 0-48 h | EMPA (100 or 500 nM) or DAPA (100 nM) for 0-48 h | EMPA ↑ the viability of cells exposed to ponatinib EMPA and DAPA ↓ the senescence of ponatinib- treated cells |
EMPA ↑ autophagic flux EMPA and DAPA ↑ proangiogenic function of endothelial cells EMPA and DAPA ↓ senescence of cells exposed to ponatinib |
| Min et al (2023)21 | Isolated neonatal mouse cardiomyocytes | Trastuzumab (2 μМ for 8 h) | EMPA (1 μM) | ↓ Lipid peroxidation ↓ Ferroptosis, DNA damage, cytosolic DNA accumulation |
|
| Dabour et al (2023)57 | HUVECs and EA.hy926 cells | Carfilzomib (0.5 μM for 24 h) | CANA, DAPA, EMPA (1-20 μM) 2 h before carfilzomib | Only CANA protected endothelial cells | AMPK restoration |
CaMKII = Ca2+/calmodulin-dependent protein kinase II; [Ca2+]i = intracellular calcium; HAEC = human aortic endothelial cell; hPBMC = human peripheral blood mononuclear cell; HUVEC = human umbilical vein endothelial cell; iROS = intracellular reactive oxygen species; NQO1 = NAD(P)H quinone dehydrogenase 1; PDGF = platelet-derived growth factor; STAT3 = signal transducer and activator of transcription 3; TLR4 = Toll-like receptor 4; VEGF = vascular endothelial growth factor; other abbreviations as in Tables 1 and 2.