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.

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 2020

R01 HL153140

8/9/2020 – 7/31/2024

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.
Co-PI Dr. Smuder is an expert in diaphragm biology and mechanisms of atrophy. Co-PI Dr. Fuller has extensive experience in preclinical SCI models of respiratory dysfunction. Consultant Dr. Dean is an authority on HBO.

NIH 2019

R01 HL144858

4/1/2019 – 3/31/2024

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 – 4/30/2024

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.

APK Research Investment Grant

3/1/2020 – 2/28/2022

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

Co-PI
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.

Past Funding Support

AHA 17GRNT33661052

7/1/2017 – 6/30/2019

"Regulation of autophagy in chemotherapy-induced heart failure"

American Heart Association; Association Wide Grant-in-Aid