Life-threatening heart damage is an adverse side effect of the cancer drug doxorubicin, damage that also limits the use of newer chemotherapeutic agents such as trastuzumab and imatinib. The ability to protect the heart from these side effects would benefit patients, including cancer survivors who are at risk of developing heart damage years later, and it also could allow safer use of these drugs at higher doses.
In a paper published Feb. 25 in theJournal of Clinical Investigation Insight, theUniversity of Alabama at Birmingham researchers show that over-expression of the enzyme heme oxygenase-1 protects the heart from doxorubicin damage by regulating mitochondrial quality control in the heart. Using a mouse model, they describe the apparent mechanisms for this protection, and they note that the benefits of heme oxygenase-1, or HO-1, may extend beyond cancer patients.
“Given that oxidative stress and alterations in mitochondrial metabolism underlie many if not most forms of cardiac failure, including heart attack, congestive heart failure, and cardiac remodeling,” the authors write, “the findings highlighted in this study are broadly applicable and may point to HO-1 expression as a general therapeutic target for patients with cardiovascular disease arising from a multitude of etiologies.”
Mitochondria are small organelles inside cells that are often called the powerhouses of the cell because they generate most of the cell’s ATP, a chemical form of energy. Oxidative stress can damage mitochondria, allowing the release of dangerous reactive oxygen species, or ROS. Thus the cell has a protective recycling mechanism called mitophagy to recognize old or damaged mitochondria and mark them for digestion into mitochondrial components.
The failure to identify and remove dysfunctional mitochondria can be quite dangerous for the cell because those mitochondria spew ROS. “What they say about ROS is that it’s just like plutonium,” said James George, Ph.D., a professor in the Division of Cardiothoracic Surgery, UAB Department of Surgery, and co-corresponding author of the paper with Anupam Agarwal, M.D., director of the Division of Nephrology, UAB Department of Medicine. “It’s really useful in the right place, but God helps you if it gets out of control.”