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Hasbullah, Jafar S.

University of British Columbia

Anthracyclines (e.g., doxorubicin) are effective chemotherapeutics used to treat a broad-spectrum of childhood and adult cancers. However, the clinical utility of anthracyclines is considerably limited by anthracycline-induced cardiotoxicity (ACT). ACT remains a significant burden in the clinic, where >50% of patients receiving anthracyclines experience some degree of ACT, initially presenting as left ventricular dysfunction, and up to 16% of patients develop heart failure. Advancements in patient genetics show substantial promise as a predictive measure of ACT. The gene variants RARG-rs2229774, UGT1A6-rs17863783, and SLC28A3-rs7853758 have the strongest evidence for association with ACT in anthracycline-treated patients. First, this thesis aimed to understand the scope of genetics, focusing on the proposed roles of genes RARG, UGT1A6, and SLC28A3 in the development and prevention of ACT. Second, I investigated the roles of UGT1A6 and RARG in the development of ACT using cellular models. The research replicated the ACT susceptibility of the UGT1A6 locus using a cellular model (HEK293) of doxorubicin-induced cytotoxicity. Further, I identified that ligand-mediated activation of RARG, using all-trans retinoic acid (ATRA) and CD1530, significantly increases the cell viability of H9c2 cardiomyoblasts. Lastly, I evaluated the efficacy of ATRA in preventing the development of cardiotoxicity using a human cardiomyocyte and a mouse model of ACT. In human cardiomyocytes, ATRA enhanced cell survival during doxorubicin exposure. The protective effect of ATRA was also observed in a mouse model (B6C3F1/J) of ACT, in which ATRA treatment improved heart function of doxorubicin-treated mice. Histological analyses also indicated that ATRA treatment reduced the pathology associated with ACT. Further, in human cardiomyocytes, ATRA induces the gene expression of retinoic acid receptors (RARG, RARB), while repressing topoisomerase-II enzyme genes (TOP2A, TOP2B), which encode for the molecular targets of anthracyclines, and repressed downstream ACT response genes. This mechanism partially explains the protective effect of ATRA and why patients presenting with dysregulation of this pathway may be susceptible to ACT. Overall, the work performed in this thesis shows that gene variants that modify ACT risk belong to critical biological pathways of ACT. Further, these molecular mechanisms also provide a unique opportunity to develop safe and effective interventions to mitigate ACT.

Text

2024-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83537

Medical Genetics

University of British Columbia

UBCV

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