# Amelioration of Doxorubicin Induced Muscle Dysfunction with Embryonic Stem Cell-Derived Exosomes

> **NIH NIH R01** · UNIVERSITY OF CENTRAL FLORIDA · 2020 · $370,721

## Abstract

Abstract
This administrative supplement is in response to notice NOT-CA-20-019 on Dementia or Alzheimer’s Disease
(AD) and is within the scope of parent grant funded by NCI R01 CA221813-03. Doxorubicin (DOX) is one of the
most effective anti-cancer drugs that causes muscle weakness and atrophy as we have proposed in the parent
grant. A recent surge in cancer survivors following DOX treatment shows cognitive deficit and developed
dementia also called “chemo brain”. Patients with chemo brain experience oxidative stress, inflammation, fog
like symtoms, and finally show DOX-induced cognitive dysfunction and dementia (DICD). It remains unknown
whether the inflammation induced cell death, known as pyroptosis (a distinct form of cell death, from apoptosis
and necrosis), occurs as a result of DICD. Our supporting preliminary data shows that treatment with DOX shows
an increase in pro-inflammatory M1 macrophages, presence of inflammatory cytokines TNF-α and IL-6 and
pyroptotic specific marker IL-1β in the DICD. We also observed a significant decrease in brain weight and size,
suggesting presence of atrophy in the chemo brain. Furthermore, our histological data shows a significant
positive pathological marker of cognitive dysfunction and dementia such as decrease in thickness of pyramidal
layer, formation of neurofibrillary tangles, Hirano bodies and cytoplasmic vacuolization in the chemo brain. Our
preliminary data shows a significant increase in AD markers (BACE1 and S100B) and brain dysfunction in chemo
brain. Therefore, we hypothesize that DOX treatment enhances infiltration of monocytes that polarizes into M1
macrophages, which triggers inflammation causing pyroptosis, brain atrophy, vacuolization which ultimately
enhances DICD and AD. Our unpublished studies as proposed in the parent grant shows ES-exos attenuate
inflammation, pyroptosis and improving muscle function. However, it is completely unknown whether ES-Exos
ameliorate DOX-induced pyroptosis and associated adverse cerebral cortex as well as hippocampal remodeling
by increasing anti-inflammatory M2 macrophages, thereby improving brain function. We propose to test these
hypotheses in two specific Aims; 1) To determine if increased presence of monocytes polarized into M1
macrophages following DOX treatment induces pyroptosis leading to cognitive dysfunction with a potential to
develop AD. 2) To demonstrate whether treatment with ES-exos cause phenoswitching of M1 macrophages into
M2 macrophages, resulting in amelioration of pyroptosis, reduced cognitive dementia and decreased severity of
AD. This application will have unique novelty to establish a link between DOX-induced muscle dysfunction and
cognitive dysfunction and dementia with a potential to develop AD while testing a potential therapy to prevent
DICD and AD.

## Key facts

- **NIH application ID:** 10122103
- **Project number:** 3R01CA221813-03S1
- **Recipient organization:** UNIVERSITY OF CENTRAL FLORIDA
- **Principal Investigator:** Rakesh C Kukreja
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,721
- **Award type:** 3
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122103

## Citation

> US National Institutes of Health, RePORTER application 10122103, Amelioration of Doxorubicin Induced Muscle Dysfunction with Embryonic Stem Cell-Derived Exosomes (3R01CA221813-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10122103. Licensed CC0.

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