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Huang, Haojun

University of British Columbia

Doxorubicin is a commonly used chemotherapy drug that treats both adult and childhood cancers, but its clinical usefulness is limited by doxorubicin-induced cardiotoxicity (DIC). The incidence of DIC increases up to 65% at cumulative doses of 550 mg/m², which leads to irreversible heart failure and death. Since some patients suffer from DIC even at low doses, genetic differences may account for some of the inter-individual variability in risk for DIC and several associated genetic variants have been identified. Among these variants, RARG-S427L is one of the top variants that shows strong evidence of association with DIC. Sodium-glucose transport protein 2 inhibitors (SGLT2i) are effective glucose-lowering medications that are indicated for type 2 diabetes mellitus treatment. SGLT2i have also been demonstrated to be cardioprotective for heart failure. We still lack ways to predict and prevent DIC. The goal of this dissertation is to investigate the impacts and mechanism of RARG-S427L variant in DIC and the potential cardioprotective effects of SGLT2i against DIC. I hypothesized that RARG-S427L increases the risk of DIC and the SGLT2i (empagliflozin) protects against DIC. To conduct this work, I developed a patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) model of DIC and used this to show that RARG-S427L increases susceptibility to DIC by orchestrating a DNA repair response to doxorubicin. Furthermore, co-treatment with empagliflozin reduced doxorubicin-induced cell death and up-regulated fatty acid metabolism-related gene expression. In summary, our findings reveal the roles of RARG-S427L in transcriptional response to doxorubicin in cardiomyocytes and identify empagliflozin as a potential cardioprotective agent against DIC, with implications for personalized risk prediction and the potential usage of empagliflozin to prevent this adverse drug reaction.

Text

2022-11-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83293

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/