Neutrophil Activation Underlies Cancer Drug's Antibacterial Effect

The bactericidal properties of the cancer drug tamoxifen have been linked to its modulation of sphingolipid biosynthesis and the effect this has on neutrophil activation and the generation of antimicrobial neutrophil extracellular traps (NETs).

Sphingosine (2-amino-4-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.

Sphingosine can be phosphorylated in vivo via two kinases, sphingosine kinase type 1 and sphingosine kinase type 2. Phosphorylation leads to the formation of sphingosine-1-phosphate, a potent signaling lipid. Sphingolipid metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate, are lipid signaling molecules involved in diverse cellular processes.

In addition to its anti-cancer activity as an estrogen receptor agonist/antagonist, tamoxifen also modulates sphingolipid biosynthesis, which has been shown to play an important role in the regulation of neutrophil activity. To examine the importance of this role, investigators at the University of California, San Diego (USA) treated cultures of human neutrophils with tamoxifen.

Results published in the October 13, 2015, online edition of the journal Nature Communications revealed that compared to untreated neutrophils, tamoxifen-treated neutrophils were better at moving toward and phagocytosing bacteria. Tamoxifen-treated neutrophils also produced approximately three-fold more neutrophil extracellular traps (NETs),

NETs provide for a high local concentration of antimicrobial components and bind, disarm, and kill microbes extracellularly and independent of phagocytic uptake. In addition to their antimicrobial properties, NETs may serve as a physical barrier that prevents further spread of the pathogens. Furthermore, delivering the granule proteins into NETs may keep potentially injurious proteins like proteases from diffusing away and inducing damage in tissue adjacent to the site of inflammation.

In follow-up experiments the investigators treated MRSA (methicillin-resistant Staphylococcus aureus)-infected mice with tamoxifen. The drug significantly protected the mice: control mice survived less than one day after infection, while about 35% of the tamoxifen-treated mice survived five days. In addition, approximately five times fewer MRSA organisms were collected from the peritoneal fluid of the tamoxifen-treated mice, as compared to control mice.

“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 senior author Dr. Victor Nizet, professor of pediatrics and pharmacy at the University of California, San Diego. “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.”

“While known for its efficacy against breast cancer cells, many other cell types are also exposed to tamoxifen. 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,” said Dr. Nizet.

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