Cardiac Glycosides, a Category that Includes Several Approved Drugs, are Found to be Senolytic

Researchers here report on the discovery that the class of drugs known as cardiac glycosides are senolytic, capable of selectively destroying the lingering senescent cells that contribute to aging and age-related disease. These cardiac glycosides are not a good candidate for use by the self-experimentation community, however, despite the existence of low-cost generic drugs in this category. They are unpleasant compounds, quite toxic, and when used in medicine come attached to a long list of side effects that sound well worth avoiding. It may nonetheless be the case that new senolytic drugs will be developed from these starting points, given the present enthusiasm for this line of work, by building upon the mechanisms to find less toxic small molecules that have the desired interactions with cellular biochemistry.

Senescence is a cellular stress response that results in the stable growth arrest of old and damaged cells. The past decade has revealed that senescent cells play important roles in a growing list of diseases from cancer, to arthritis, atherosclerosis, and many more. Previous studies have shown that the specific elimination of senescent cells with drugs or using genetic tricks makes mice live healthier for longer. Eliminating senescent cells results in improvements in fibrosis, cataracts, atherosclerosis and in more than 20 other diseases.

After examining a library of drugs that are already used in the clinic and testing them on normal and senescent cells, the researchers identified ouabain as a potential candidate to selectively kill senescent cells. Ouabain belongs to a family of natural compounds called cardiac glycosides that include also digoxin and digitoxin. Cardiac glycosides are used in the clinic to treat cardiac arrythmias and atrial fibrillation. In this study it was found that cardiac glycosides selectively eliminate many types of senescent cells, including when senescence has been triggered by irradiation, cancer itself, or chemotherapeutic drugs - such as etoposide or doxorubicin. The fact that ouabain can eliminate different types of senescent cells emphasises its potential as a broad spectrum senolytic.

"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."

Link: https://lms.mrc.ac.uk/repurposing-heart-drugs-to-target-cancer-cells/

Comments

>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."

that applies also to dasatinibg plus quercetin combination.

I would say that any toxic drug has some senolytic activity. If we are fancy we can even invent a term "senotoxic" to indicate that something kills senescent cells but with a very high collateral damage.

Another interesting question to ask is how do different sonlitycs compound when used in combination.

Posted by: cuberat at October 22nd, 2019 8:11 AM

This is far from the first time that we hear news of drugs with senolytic effects which are cardiotoxic - in the case of digoxin, severely so - that's why it's still standard of care in CHF even though it was on the market in the 1930's

Natural products are great initial screening proxies, but there are millions of compounds one may want to examine before starting with the most poisonous

Posted by: David Permisov at October 22nd, 2019 8:22 AM

I think this xkcd comic is just as pertinent to senolytics as it is to anti-cancer agents.

https://xkcd.com/1217/

Posted by: Arcanyn at October 25th, 2019 12:57 AM

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