Research

Doxorubicin

Doxorubicin (DOX) is a highly effective antitumor agent used for the treatment of a wide range of cancers. Unfortunately, DOX treatment results in cytotoxic side effects due to its accumulation within off-target tissues. DOX-induced cellular toxicity occurs as a result of increased oxidative damage, resulting in apoptosis and cell death.

Mechanism of Action: Oxidative Stress

There are several ways in which DOX can produce reactive oxygen species (ROS) (Fig. 2). First, a one-electron reduction in the DOX quinone structure leads to the formation of a semiquinone free radical intermediate. The unpaired electron of the semiquinone moiety can be donated to oxygen to form superoxide radicals. Second, metabolism of DOX via cleavage of the sugar residue and reduction in the carbonyl group at C-13 to produce doxorubicinol also results in ROS generation through redox cycling and increased levels of free iron. Third, DOX can generate ROS through a direct interaction with iron or other metal ions. Specifically, DOX can form a complex with iron that is capable of reacting with O2 or H2O2 to produce free radicals. Superoxide and its decomposition products can initiate lipid peroxidation and cause injury to healthy tissue.

Exercise-Induced Protection Against DOX

While there is no standard-of-care practice to prevent DOX-induced toxicity to healthy organs, exercise has been shown to prevent cellular dysfunction when combined with DOX chemotherapy. Endurance exercise stimulates numerous biochemical adaptations that promote a healthy phenotype in several vulnerable tissues without affecting the antineoplastic properties of DOX. Therefore, for the development of an effective strategy to combat the pathological effects of DOX, it is important to determine the appropriate exercise regimen to prescribe to cancer patients receiving DOX therapy and to understand the mechanisms responsible for exercise-induced protection against DOX toxicity to noncancer cells.

Particle-based Delivery of ATRA to Promote Muscle Recovery Following Prolonged Immobilization

Disuse muscle atrophy secondary to acute illness or injury prolongs recovery and increases risk of permanent disability as a result of reduced muscle strength and myofiber damage upon reambulation. However, there are no pharmacotherapies to support muscle growth and repair following prolonged immobility. We propose that all-trans retinoic acid (ATRA) may support recovery of atrophied muscle via modulation of satellite cells and macrophages. Clinical application of ATRA is hindered by solubility, stability, and the need for high systemic doses. Therefore, we developed poly(lactide-co-glycolide) (PLG) particles for local injection and extended release of ATRA (ATRA-PLG) and investigated the impact of ATRA-PLG on muscle recovery from disuse atrophy in adult mice following 10 days of hindlimb cast immobilization. A single administration of ATRA-PLG to the facia surrounding the calf muscle, at the time of cast removal, accelerates recovery of soleus muscle cross-sectional area. This is associated with decreased tissue damage, increased expression of macrophage scavenger receptors CD206 and CD163, and decreased CD68 and IL-6. The data suggest that ATRA-PLG modulation of macrophages may limit inflammation and secondary injury to the atrophied muscle during the early stages of recovery, which then requires a lower repair response, and this translates to accelerated recovery of cross-sectional area.

Hyperbaric Oxygen Therapy (HBO) and Respiratory Neuromuscular Recovery after Spinal Cord Injury (SCI)

Oxidative damage to the diaphragm as a result of cervical spinal cord injury (SCI) promotes muscle atrophy and weakness. Respiratory insufficiency is the leading cause of morbidity and mortality in cervical spinal cord injury (SCI) patients, emphasizing the need for strategies to maintain diaphragm function. Hyperbaric oxygen (HBO) increases the amount of oxygen dissolved into the blood, elevating the delivery of oxygen to skeletal muscle and reactive oxygen species (ROS) generation. It is proposed that enhanced ROS production due to HBO treatment stimulates adaptations to diaphragm oxidative capacity, resulting in overall reductions in oxidative stress and inflammation.

HBO is routinely used in clinical practice for treatment of ischemic diseases, to promote wound healing and for decompression sickness. There is also growing preclinical evidence indicating therapeutic potential for HBO treatment to enhance recovery of skeletal muscle health after injury. Rodent studies confirm that both acute and chronic exposure to HBO can provoke substantial increases in skeletal muscle antioxidant enzyme expression. Given that cervical SCI increases oxidative stress in the diaphragm and antioxidant therapy can mitigate diaphragm atrophy, we reasoned that HBO therapy could promote diaphragm muscle health following SCI.

Ongoing Projects

NIH 2019

R01 HL144858

4/1/2019 – 3/31/2026

Doxorubicin cardiotoxicity and the protective effects of exercise

The goal of this proposal is to establish the effects of these transport proteins in mediating the exercise-induced extrusion of DOX from the heart, and to determine their therapeutic potential to prevent DOX-induced cardiac dysfunction. We will accomplish this by testing the following specific aims:
Specific Aim 1) will determine if exercise-induced protection against DOX toxicity is dependent on increased levels of mitochondria-localized ABC transporters; Specific Aim 2) will determine if overexpression of mitochondrial ABC transport proteins in the heart is sufficient to reduce cardiac DOX accumulation and prevent DOX-induced cardiotoxicity.
The long-term goal of this project is to identify biological targets that will assist in the development of a therapeutic strategy to reduce the risk of cardiovascular disease in cancer patients. The results from this study will advance the understanding of the molecular basis of DOX-induced myocardial toxicity and serve as the foundation for future translational studies to generate preventative strategies.

NIH 2019

R01 HL146443

5/1/2019 – 4/30/2026

Doxorubicin-induced respiratory dysfunction and the protective effects of exercise

The goal of this proposal is to establish the effects of these transport proteins in mediating the exercise-induced extrusion of DOX from the diaphragm, and to determine their therapeutic potential to prevent DOX-induced respiratory dysfunction. We will accomplish this by testing the following specific aims:
Specific Aim 1) will determine if exercise-mediated protection against DOX-induced respiratory dysfunction is dependent on increased levels of mitochondria-localized ABC transport proteins; Specific Aim 2) will determine if overexpression of mitochondrial ABC transport proteins in the diaphragm is sufficient to reduce DOX accumulation and prevent DOX-induced respiratory dysfunction.

Veterans Health Administration 2024

RX004564-02

5/1/2024 – 4/30/2028

Macrophage-targeted microparticles for the regeneration of atrophied muscle

Muscle weakness in VA patients most commonly results from inactivity related to injury, illness, or surgery. Even with aggressive rehabilitation, bouts of enforced skeletal muscle inactivity can lead to atrophy and loss of function that persist long after remobilization. While pharmacotherapies might improve outcomes for many veterans suffering from loss of function secondary to disuse atrophy, none exist. Since age- related loss of muscle function accelerates further loss of function and increases risk of disability, development of a pharmacotherapy that enables full recovery of function would be transformative for veterans and the general population. Effective recovery of atrophied skeletal muscle is dependent upon macrophages. First, macrophage inflammation directs satellite cells to fuse with damaged fibers to facilitate repair. Then, macrophage regenerative factors resolve inflammation and promote muscle growth. Therefore, a pharmacotherapy is needed that can specifically target these cells within the skeletal muscle. We met this challenge by developing polymer particles for localized, extended release of all-trans retinoic acid (ATRA-PLG). ATRA is in broad use clinically for indications other than muscle wasting, but our data indicate delivery of ATRA-PLG to the facia of atrophied muscle restores muscle fiber size, improves mobility, increases IGF-1, and decreases IL-6 in the early phase of recovery. Also, in vitro studies indicate ATRA-PLG induces macrophages to secrete IGF-1. Therefore, our central hypothesis is that administration of ATRA-PLG to atrophied muscle enhances 1) skeletal muscle recovery and 2) the macrophage regenerative response. We will test this hypothesis by inducing muscle atrophy with cast immobilization in mice and then injecting ATRA-PLG with release kinetics that match the time course of muscle recovery when the cast is removed.
Specific Aim 1 will determine if ATRA-PLG delivery accelerates functional recovery of skeletal muscle after remobilization.
Specific Aim 2 will determine if ATRA-PLG delivery enhances the macrophage regenerative response in skeletal muscle recovering from disuse.

APK Research Investment Grant

9/1/2025 – 8/31/2026

Mechanisms for doxorubicin cardiac accumulation and dysfunction

Major goals: to test the hypothesis that DOX-induced cardiovascular endothelial permeability and cardiac uptake is critically dependent on endothelial expression of the tight junction protein ZO-1.

Past Funding Support

NIH 2020

R01 HL153140

8/9/2020 – 7/31/2025

Hyperbaric oxygen therapy mitigates respiratory neuromuscular pathology after spinal cord injury

Hyperbaric oxygen (HBO) therapy involves brief (≤1 hr) exposure to pressurized oxygen at ≤3 ATM and is used frequently for wound healing and decompression sickness. Our preliminary data and literature reports have led to the central hypothesis that HBO, delivered in the acute phases (days to weeks) after cervical spinal cord injury (SCI), attenuates diaphragm atrophy and dysfunction, reduces cervical spinal cord pathology, and improves respiratory neuromuscular recovery.
Aim 1 will test the hypothesis that HBO therapy during acute through sub-acute phases after cervical SCI reduces diaphragm atrophy and improves contractility. The hypothesis will be tested with histological, molecular and functional evaluation of the diaphragm. To test oxidative mechanisms, antisense oligonucleotides will be used to block translation of specific antioxidants during HBO therapy. To determine if antioxidant mechanisms are sufficient to explain the HBO therapeutic effects, we will overexpress specific antioxidants using adeno-associated virus (AAV). Aim 2 will test the hypothesis that the neuroprotective impact of HBO therapy during acute through sub-acute phases after cervical SCI leads to improved phrenic motor recovery. The hypothesis will be tested with histological, molecular, and neurophysiological methods (direct phrenic nerve recordings and diaphragm electromyography). As in Aim 1, mechanistic studies will utilize antisense oligonucleotides and AAV strategies to modulate antioxidant formation in the spinal cord.

APK Research Investment Grant

3/1/2020 – 2/28/2022

Development of a translational model to study vascular complications of breast cancer chemotherapy

Major goals: To evaluate vascular function in a cohort of patients receiving breast cancer chemotherapy and establish a clinically relevant rodent model that accurately mimics the patient condition.

AHA GRNT33661052

7/1/2017 – 6/30/2019

Regulation of autophagy in chemotherapy-induced heart failure

Major goals: to test the two-prong central hypothesis that prevention of DOX-induced autophagy elicits cardioprotection as a result of: 1) a positive feedback loop between autophagy and increased ROS production; and 2) increased antioxidant enzyme capacity.

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