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Found 1 Presentation For Request "1969p"
1969P - The SGLT2 inhibitor dapagliflozin enhanced anticancer activities and exerts cardioprotective effects against doxorubicin and trastuzumab toxicity through TLR4, MyD88, NF-kB signaling and NLRP3 inflammasome pathway
- Nicola Maurea (Napoli, Italy)
Abstract
Background
The clinical trial "DECLARE-TIMI 58", demonstrated that dapagliflozin, a SGLT2 inhibitor, reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus. We aimed to study if dapagliflozin could exerts cardioprotective effects in doxorubicin and trastuzumab-induced cardiotoxicity and increase their anticancer effects in HER2+ human breast cancer cells.
Methods
HL-1 cardiomyocytes and HER2+ human breast cancer cells were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin at 50 nM. Determination of cell viability was performed through MTS assay and the study of lipid peroxidation and intracellular Ca2+ homeostasis were made by spectrofluorometric analysis. Anti-inflammatory studies were also performed (activation of NLRP3 inflammasome; expression MyD88; transcriptional activation of p65/NF-κB and secretion of pro-inflamamtory cytokines (Interleukins 1β, 8 and 6). Moreover, mTORC1 /Fox01/3a expression studies were performed through western blot.
Results
Dapagliflozin increases significantly the cardiomyocytes viability during exposure to doxorubicin and trastuzumab and ehnance their anticancer activity in breast cancer cells. Its cardioprotective properties are explainable by the reduction of intracellular Ca2+ overload and lipid peroxidation. Moreover, cardiomyocytes and human cancer cells exposed to dapagliflozin during anticancer drugs have a reduced expression of pro-inflammatory cytokines involved in cardiotoxicity. Notably, dapagliflozin reduces p65-NF-κB activation and inhibits the expression of NLRP3 inflammasome. mTORC1 /Fox01/3a expression were also reduced after treatment with dapagliflozin.
Conclusions
Dapagliflozin demonstrated cardioprotective properties during doxorubicin and trastuzumab exposure, increasing their anticancer effects against breast cancer cells. The main biochemical effects of dapagliflozin are related to MYD88, NLRP3 complex and mTORC1 /Fox01/3a mediated apoptosis.
Legal entity responsible for the study
The authors.
Funding
Italian Ministry of Health; Ricerca corrente “Cardiotossicità dei trattamenti antineoplastici: Identificazione precoce e strategie di cardioprotezione ”Codice progetto: M1/5-C.
Disclosure
All authors have declared no conflicts of interest.