Can Tamoxifen Help the Body Fight MRSA?

Researchers report that the common breast cancer drug tamoxifen enhanced neutrophil antibacterial function by elevating chemotaxis, phagocytosis, and neutrophil extracellular trap formation in their recent study. It also increased survival of methicillin-resistant Staphylococcus aureus (MRSA) in mice.

“New approaches to antibiotic-resistant pathogens are urgently needed, as they exert a tremendous and increasing burden on the public health, with significant morbidity and mortality,” said senior author Dr. Victor Nizet, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego. “Also, continual exposure to broad-spectrum antibiotics damages the healthy microbiome, with other adverse consequences, including Clostridium difficile and fungal infections.”

According to the author, “We are generally interested in ‘outside-the-box’ approaches to infectious disease therapy in this era of increasingly antibiotic-resistant pathogens. By thinking of bacterial infections in the context of the pathogen-host interaction, new options for treatment emerge.”

These new approaches, which include virulence factor inhibitors to sensitize the bacteria to innate immune killing or drugs that work on the white blood cells to boost their antimicrobial activity, “could be more specific for the target pathogen, or the focus of infection, and preserve the normal flora on the healthy skin and mucosal surfaces,” he added.  

Emerging evidence has indicated that tamoxifen not only blocks the estrogen receptor, which makes it effective in breast cancer treatment and prophylaxis, but also has other cellular effects.

Dr. Nizet and colleagues therefore examined the drug’s effect on human neutrophils and in a mouse model.

“Tamoxifen stimulation enhances several pro-inflammatory pathways in human neutrophils, including chemotaxis, phagocytosis and neutrophil extracellular trap (NET) formation,” the authors wrote of their findings.

Further, researchers infected mice with MRSA one hour after treatment with either tamoxifen or placebo; the mice were treated again one and eight hours after infection. More than one-third of the tamoxifen-treated mice survived five days after infection, while none of the placebo-treated mice survived longer than one day after infection.

“Tamoxifen has these effects not by blocking the estrogen receptor (for which it is used in breast cancer treatment and prophylaxis), but by modulating the levels of a neutrophil lipid called ceramide, which is known to control neutrophil activation,” Dr. Nizet explained. “Because of these properties, neutrophils treated with tamoxifen killed bacteria better in a test tube and protected mice against severe MRSA infection.”

“We believe that a lot of current drugs that are in the clinics to treat other medical conditions may have important effects on white blood cell function during acute infection,” he said. “In earlier work, we discovered immune-boosting effects of statins, taken by tens of millions of individuals for cholesterol lowering, and prolyl hydroxylase inhibitors that stabilize the transcriptional regulator hypoxia-inducible factor, similar to those currently in advanced clinical trials for anemia therapeutics.”

Dr. Nizet noted that a trial of patients with antibiotic-resistant infections in which tamoxifen would be added to the current standard of care (i.e. antibiotics) compared with standard-of-care alone is the “proper approach moving forward,” considering the frequent off-label uses of approved drugs for patients who are failing conventional therapy.

The study’s ultimate take-home message for clinicians, according to Dr. Nizet, is that “By unlocking the medical cabinet and studying the activities of drugs in the context of infection, new targets and opportunities for therapy might be revealed.”

This research was published in Nature Communications and was funded in part by the National Institutes of Health.

-Meredith Edwards White

Reference:

1. Corriden R, Hollands A, Olson J, et al. Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide. Nat Commun. 2015;6:8369.