Cellular aging (that scientists call senescence) is a natural process that allows the body to filter out old and damaged cells that no longer fulfill their purpose. However, senescence sometimes malfunctions, and some researchers believe that this can contribute to the growth and spread of cancer tumors. This is mostly due to a bad lifestyle, with hard tobacco smoking, heavy alcoholic drinking, poor diet and unmanaged stress. All these factors contribute to the production of reactive oxidant species (ROS), which may damage proteins and the genetic material, leading to many health problems, like diabetes or cancer, and of course cellular aging. Thus, researchers have been hard at work to find new drugs, which they term senolytics, that can kill senescent cells that may pose a threat to health. Previous studies in animal models have shown that senolytics could have a number of benefits, including keeping individuals healthier for longer and prolonging life span. Some senolytic drugs include natural polyphenols like fisetin and quercitin, along with synthetic drugs like dasatinib and navitoclax.
Some senolytics, such navitoclax, have demonstrated some effectiveness in treating blood cancers, including leukemia and lymphoma. Yet navitoclax can also have serious side effects, including thrombocytopenia, the abnormally low platelet levels in the blood. Recently, however, researchers from the MRC London Institute of Medical Sciences in the United Kingdom may have identified an alternative senolytic — in the form of an existing heart drug known as ouabain. In the study paper that appears in the journal Nature Metabolism, the investigators explain that they experimented with various existing drugs, testing them on both healthy and senescent cells to see how they would act. In doing so, they closed in on ouabain, a compound that forms part of the same class of drugs as digoxin and digitoxin, namely cardiac glycosides. These steroidal molecules are usually highly toxic for certain tissues and are mostly active in the heart. Such compounds can treat heart conditions, including cardiac arrhythmias and atrial fibrillation, both of which have characteristics of irregular or abnormal heartbeats.
Sources of these substances is wide in Nature, and common plants contain them in various amounts. Among them the Lily of the Valley (Convallaria majalis), purple foxglove (Digitalis purpurea), motherwort (Leonurus cardiaca), oleander tree (Nerium oleander) and strophantus vine (Strophanthus kombe), from which derive ouabain and other strophantines. These plants are deadly due to the content of these glycol-steroids, which must be used in doses lesser than one milligram. It was reported at least thirty years ago that ouabain and other similar molecules were active in killing some strains of leukemia in culture. But they never entered the clinical application. The research team found that ouabain can selectively kill different types of aging cells, including those that have become senescent because of cancer, or due to exposure to radiotherapy or chemotherapy drugs such as etoposide and doxorubicin. This makes ouabain a potential candidate for use as a broad spectrum senolytic: a drug that targets a very varied array of aging cells.
The researchers reached this conclusion by testing the drug in vivo, in aging mice, and “in precancerous lesions in the liver and upon radiotherapy. These molecules are known to act through modulation of the sodium channel in the cellular membrane (Na-K ATPase), but other possible cellular targets have been speculated. For example, nerioside from oleander tree inhibits the activation of the survival transcription factor NF-kB; and other cardiosteroids may regulate second messenger molecules like cyclic AMP. Prof. Jesùs Gil, senior author, pointed out: “These drugs are already used in the clinic, so they could be repurposed to treat a long list of diseases, including cancer. This is something we are keen to explore with our clinical collaborators. Moreover, many patients are being treated with digoxin, and an epidemiologist could look retrospectively and ask the question of whether those patients who were treated with digoxin are doing better than those who weren’t.” Thus, future studies could compare the health outcomes for people who have received treatment with cardiac glycosides versus those who have not, making it easier to confirm whether this class of drugs has true potential as a senolytic.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Triana-Martínez F et al. Nat Commun. 2019 Oct; 10(1):4731.
Hickson LJ et al. EBioMedicine. 2019 Sep; 47:446-456.
Mavrogonatou E et al. Semin Cancer Biol. 2019 Jun 28.