TARGETING DOXORUBICIN-INDUCED MITOCHONDRIAL FAILURE IN MESENCHYMAL STEM CELLS WITH METFORMIN

As of 2014, there are approximately 14.5 million cancer survivors within the United States and this populationis projected to grow to 19 million by 2024. Cancer survivors exhibit an accelerated aging phenotype that ishypothesized to be a result of their exposure to chemotherapy. Despite the preponderance of evidencesuggesting that this accelerated aging phenotype happens, there are few basic science initiatives poised tostudy the underlying molecular mechanisms and their therapeutic implications. Cancer survivors haveincreased bone marrow adiposity, central obesity, serum leptin and triglyceride concentrations, which depict aclinical picture of metabolic dysfunction. These clinical observations suggest that chemotherapy disturbs typicaladipose biology. Little is understood about how chemotherapy and DNA-damaging agents can alter the agingof adipose tissue. Adipocytes are post-mitotic and adipogenesis depends on mesenchymal stem cells (MSCs)in these tissues. In addition, most DNA damaging agents damage mitochondrial DNA (mtDNA) more thannuclear DNA, owing to poor mtDNA damage repair. For these reasons, we propose chemotherapy affectsMSC mitochondria, allowing for a persistent insult to mitochondrial function after chemotherapy exposure.Mitochondrial health is able to modulate adipogenesis, which may allow damaged mitochondria to driveadipogenesis in MSCs, explaining the clinical phenotype of metabolic dysfunction in cancer survivors.Doxorubicin (DOX), a commonly used DNA damaging agent, has well documented effects on the mitochondriaof the heart. These effects on the heart can be summarized as a mitochondrial bioenergetics failure, marked byincreased reactive oxygen species (ROS) production, decreased mitochondrial number, and impaired ATPproduction. Further, metformin (MET) has been found to ameliorate the severity of DOX-induced cardiac injuryin various experimental models. Therefore, we hypothesize that DOX treatment of MSCs induces mitochondrialdysfunction that accelerates age-related adipogenesis, which may be ameliorated by metformin. To test theseconcepts, we will use a series of in vitro and ex vivo approaches to study the aging of MSCs and how DOXcontributes to abnormalities in MSC aging, as well as in vivo approaches to study adipose distribution andadipocyte hypertrophy and hyperplasia in our pediatric mouse model of DOX exposure. We will also examineMET's ability to rescue this phenotype Our specific aims are (1) to demonstrate whether DOX treatmentinduces mitochondrial damage in MSCs, which accelerates adipogenesis in vitro and ex vivo, (2) to define thein vitro and ex vivo roles of MET on MSC adipogenesis following DOX exposure, and (3) to establish theeffects of DOX and MET treatment on bone marrow adiposity, lipodystrophy, serum leptin, and serumtriglycerides. Upon completion, this study may identify MSCs as a mediator of chemotherapy's effects onadipogenesis, demonstrate the mitochondrial effect of chemotherapy on somatic cells, and identify MET as anFDA approved therapeutic in the treatment of late side effects of chemotherapy.