A team led by Massachusetts General Hospital (MGH) researchers has identified several FDA-approved drugs that can shift cellular energy metabolism processes in animals. They also note that that the nutrient-sensitized screening technique they used may prove useful for understanding gene function and drug action within the context of energy metabolism.
Their findings are published online in Nature Biotechnology in paper titled “Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis.”
“Shifts in cells' energy production pathways take place naturally during development and in response to demanding activities. They are also known to be involved in several disease states,” explains Vamsi Mootha, M.D., of the MGH Center for Human Genetic Research, who led the study. “We wanted to identify compounds that can safely induce this shift—those that have previously been discovered are too toxic—and investigate their therapeutic potential in animal models.”
Cells convert nutrients into energy either by glycolysis or through cellular respiration. In cancer cells and other rapidly proliferating cells, energy is produced predominantly by glycolysis, suggesting that a shift away from that mechanism might suppress tumor growth. Previous animal studies suggested that a reduction in mitochondrial respiration could mimic a process called ischemic preconditioning, in which brief episodes of ischemia actually protect tissue against being damaged if its blood supply is later cut off completely.
To search for compounds that shift cells from respiration to glycolysis, Dr. Mootha's team devised a new screening strategy. They cultured skin cells in two different nutrient environments: glucose, which provides energy through both glycolysis and respiration, or galactose, which forces cells to rely on mitochondrial respiration alone. A drug that redirects energy metabolism from respiration to glycolysis would stop growth in the galactose-cultured cells but would have little effect on cells grown in glucose.
Their initial screen reportedly included almost 3,700 compounds including nearly half of all FDA-approved drugs. They identified several drugs known to inhibit cellular respiration on one end of the scale and several anticancer drugs that halt the growth of rapidly proliferating cells at the other.
Because most agents known to mimic ischemic preconditioning in animal models are too toxic to use in human patients, the researchers were most interested in finding drugs that cause subtle metabolic shifts. The screen identified eight approved drugs that produced a less pronounced but still significant shift away from cellular respiration. One of those agents was meclizine, an over-the-counter drug used to treat nausea and vertigo, suggesting that it passes the blood-brain barrier with few negative side effects.
To investigate meclizine's potential to prevent tissue damage in heart attack or stroke, Dr. Mootha's group collaborated with University of Rochester researchers who had developed rat models of heart attack damage and an MGH pathology team with a mouse model of stroke damage. Blinded experiments using both animal models showed that pretreatment with meclizine dramatically reduced ischemic damage to cardiac cells in the heart attack model and to brain cells in the stroke model. They also found that meclizine's ischemia protective effects do not appear to involve its known mechanisms.
Dr. Mootha stresses that much additional study is needed. “Before we can think about human studies, we need to do rigorous animal testing to determine optimal, safe dosing regimens and learn more about how this drug works.” He also notes that the drug-screening strategy developed by his team could help to identify previously unsuspected beneficial or detrimental effects of other approved drugs.