# Mechanism and Prevention of Doxorubicin-Induced Lymphedema

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2022 · $267,665

## Abstract

PROJECT SUMMARY/ABSTRACT
 Lymphedema is a major complication after radiation and/or surgery for breast cancer. Unfortunately, there
are no medications to effectively treat it. Serious complications include pain, lymphangitis, cellulitis, ulcers, and
the development of malignant lymphangiosarcomas. Doxorubicin (DOX) is a central chemotherapeutic agent for
treating breast cancer, but it increases the risk of lymphedema by 4- to 5-fold. The mechanism by which DOX
contributes to the development of lymphedema is unknown, but it is thought to relate to its cytotoxic action.
However, we propose that clinical concentrations of DOX directly inhibit the rhythmic contractions of lymph
vessels (LVs) that propel lymph fluid from tissues back to the heart to prevent lymphedema. These contractions
are tightly controlled by the calcium concentration and redox state in LVs. High-resolution in vivo imaging also
reveals that systemically administered DOX profoundly reduces lymph flow. The suppression of LV contractile
function by DOX is largely prevented by both dantrolene (DANT), a clinically available blocker of ryanodine
receptors (RYRs), and MitoTEMPO, a mitochondrial-specific reactive oxygen species (mitoROS) scavenger.
These data, along with knowledge that DOX activates RYRs and induces mitochondrial dysfunction in striated
muscle and recent discoveries of functional RYRs in LVs, have led us to hypothesize that: DOX acutely opens
RYRs to increase cytosolic calcium and mitoROS in lymph muscle cells (LMCs), resulting in the loss of
LV contractions and inducing lymphostasis and lymphatic injury. Accordingly, we will explore whether
DANT, an FDA-approved RYR blocker, can prevent DOX-induced lymphatic dysfunction. Three aims will
use an integration of techniques to explore this hypothesis and will rely on protein and functional analysis of
isolated lymph muscle cells and whole LVs, use optical imaging to assess volumetric lymph flow in vivo in
response to DOX and RYR blockade, and investigate the utility of DANT as a potential therapeutic in a rat breast
tumor model. Aim 1 will quantify the gene and protein expression profiles of RYR subtypes and determine
whether DOX activates RYRs to increase cytosolic calcium and mitoROS generation as a mechanism of
inhibiting LV contractions. Aim 2 will evaluate if DANT represents a potential therapeutic option to prevent DOX-
induced suppression of lymph flow and prevent DOX-induced lymphatic injury. Aim 3 will investigate the effects
of DANT on the anticancer activity of DOX in a rat model of breast cancer. Thus, we plan to explore RYRs as
new therapeutic targets for DOX-related lymphedema and evaluate whether RYR blockers can be repurposed
as anti-lymphedema medications.

## Key facts

- **NIH application ID:** 10487486
- **Project number:** 5P20GM109005-08
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Amanda Stolarz
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $267,665
- **Award type:** 5
- **Project period:** 2015-06-24 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487486

## Citation

> US National Institutes of Health, RePORTER application 10487486, Mechanism and Prevention of Doxorubicin-Induced Lymphedema (5P20GM109005-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487486. Licensed CC0.

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