# Targeting Doxorubicin-Induced Mitochondrial Failure in Mesenchymal Stem Cells with Metformin

> **NIH NIH F30** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $43,503

## Abstract

Abstract
As of 2014, there are approximately 14.5 million cancer survivors within the United States and this population
is projected to grow to 19 million by 2024. Cancer survivors exhibit an accelerated aging phenotype that is
hypothesized to be a result of their exposure to chemotherapy. Despite the preponderance of evidence
suggesting that this accelerated aging phenotype happens, there are few basic science initiatives poised to
study the underlying molecular mechanisms and their therapeutic implications. Cancer survivors have
increased bone marrow adiposity, central obesity, serum leptin and triglyceride concentrations, which depict a
clinical picture of metabolic dysfunction. These clinical observations suggest that chemotherapy disturbs typical
adipose biology. Little is understood about how chemotherapy and DNA-damaging agents can alter the aging
of 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 than
nuclear DNA, owing to poor mtDNA damage repair. For these reasons, we propose chemotherapy affects
MSC 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 drive
adipogenesis 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 mitochondria
of the heart. These effects on the heart can be summarized as a mitochondrial bioenergetics failure, marked by
increased reactive oxygen species (ROS) production, decreased mitochondrial number, and impaired ATP
production. Further, metformin (MET) has been found to ameliorate the severity of DOX-induced cardiac injury
in various experimental models. Therefore, we hypothesize that DOX treatment of MSCs induces mitochondrial
dysfunction that accelerates age-related adipogenesis, which may be ameliorated by metformin. To test these
concepts, we will use a series of in vitro and ex vivo approaches to study the aging of MSCs and how DOX
contributes to abnormalities in MSC aging, as well as in vivo approaches to study adipose distribution and
adipocyte hypertrophy and hyperplasia in our pediatric mouse model of DOX exposure. We will also examine
MET's ability to rescue this phenotype Our specific aims are (1) to demonstrate whether DOX treatment
induces mitochondrial damage in MSCs, which accelerates adipogenesis in vitro and ex vivo, (2) to define the
in vitro and ex vivo roles of MET on MSC adipogenesis following DOX exposure, and (3) to establish the
effects of DOX and MET treatment on bone marrow adiposity, lipodystrophy, serum leptin, and serum
triglycerides. Upon completion, this study may identify MSCs as a mediator of chemotherapy's effects on
adipogenesis, demonstrate the mitochondrial effec...

## Key facts

- **NIH application ID:** 9973040
- **Project number:** 5F30AG057213-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Brian Iskra
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $43,503
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973040

## Citation

> US National Institutes of Health, RePORTER application 9973040, Targeting Doxorubicin-Induced Mitochondrial Failure in Mesenchymal Stem Cells with Metformin (5F30AG057213-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973040. Licensed CC0.

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