Researchers have found that tamoxifen is not only an estrogen receptor modulator for the treatment of breast cancer, but it also boosts bactericidal capacity against methicillin-resistant Staphylococcus aureus (MRSA) and a variety of other pathogens, according to a study published online October 14, 2015 in Nature Communications.
“The threat of multidrug-resistant bacterial pathogens is growing, yet the pipeline of new antibiotics is drying up. We need to open the medicine cabinet and take a closer look at the potential infection-fighting properties of other drugs that we already know are safe for patients,” said the study’s senior author Victor Nizet, MD, professor of pediatrics at University of California San Diego School of Medicine and professor of pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences, in San Diego, CA.
He explained, “Through this approach, we discovered that tamoxifen has pharmacological properties that could aid the immune system in cases where a patient is immunocompromised or where traditional antibiotics have otherwise failed.”
One of tamoxifen’s other properties—in addition to targeting the estrogen receptor—is influencing the production of sphingolipids. One sphingolipid in particular, ceramide, plays a role in regulating the activity of neutrophils.
“Tamoxifen’s effect on ceramides led us to wonder if, when it is administered in patients, the drug would also affect neutrophil behavior,” said first author Ross Corriden, PhD, project scientist in the UC San Diego School of Medicine Department of Pharmacology.
To test their theory in vitro, the researchers incubated human neutrophils with tamoxifen. Compared against untreated neutrophils, the tamoxifen-treated neutrophils showed enhanced chemotaxis and phagocytosing of bacteria.
Tamoxifen-treated neutrophils also produced approximately three-fold more neutrophil extracellular traps (NETs)—a mesh of DNA, antimicrobial peptides, enzymes, and other proteins that neutrophils release to ensnare and kill pathogens. Further studies linked the tamoxifen effect to its ability to influence neutrophil ceramide levels.
The researchers next performed in vivo testing of tamoxifen’s immune-boosting effect in a mouse model. One hour after intraperitoneal treatment with either tamoxifen or a control (corn oil), the researchers infected mice with a lethal dose of MRSA. The researchers treated the mice again with tamoxifen or the control at 1 hour and then at 8 hours after infection, and monitored the mice.
About 35% of the tamoxifen-treated mice survived for 5 days, while none of the control mice survived longer than 1 day after infection. Also, approximately 5 times fewer MRSA were collected from the peritoneal fluid of the tamoxifen-treated mice compared with the control mice.
“While known for its efficacy against breast cancer cells, many other cell types are also exposed to tamoxifen,” Dr. Nizet said. “The ‘off-target effects’ we identified in this study could have critical clinical implications given the large number of patients who take tamoxifen, often every day for years.”
However, the researchers acknowledged at least two limitations to their study. First, while tamoxifen was effective against MRSA in this trial, other pathogens—including those that have evolved methods for evading NET capture—may show different outcomes. Second, other studies have linked excessive NET production to inflammatory disease, such as vasculitis and bronchial asthma. So, in the absence of infection, too many NETs could be harmful.