Washington | Researchers have found that a breast cancer drug gives white blood cells a boost, which may better enable them to fight antibiotic-resistant bacteria. Treatment with the drug tamoxifen in mice also enhances clearance of the antibiotic-resistant bacterial pathogen MRSA (methicillin resistant Staphylococcus aureus) and reduces mortality.
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, said senior author Victor Nizet, professor at the University of California, San Diego in US. Tamoxifen targets the estrogen receptor, making it particularly effective against breast cancers that display the molecule abundantly. But some evidence suggests that tamoxifen has other cellular effects that contribute to its effectiveness, too. For example, tamoxifen influences the way cells produce fatty molecules, known as sphingolipids, independent of the estrogen receptor. Sphingolipids, and especially one in particular, ceramide, play a role in regulating the activities of white blood cells known as neutrophils.
Tamoxifen’s effect on ceramides led us to wonder if, when it is administered in patients, the drug would also affect neutrophil behaviour, said first author Ross Corriden, from the UC San Diego School of Medicine. To test their theory, the researchers incubated human neutrophils with tamoxifen. Compared to untreated neutrophils, they found that tamoxifen-treated neutrophils were better at moving toward and phagocytosing, or engulfing, 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 spew out to ensnare and kill pathogens.
Treating neutrophils with other molecules that target the estrogen receptor had no effect, suggesting that tamoxifen enhances NET production in a way unrelated to the estrogen receptor. Further studies linked the tamoxifen effect to its ability to influence neutrophil ceramide levels. The team also tested Tamoxifen’s immune-boosting effect in a mouse model. One hour after treatment with tamoxifen or a control, the researchers infected mice with MRSA. They treated the mice again with tamoxifen or the control one and eight hours after infection and monitored them for five days.
Tamoxifen significantly protected mice. None of the control mice survived longer than one day after infection, while about 35 per cent of the tamoxifen-treated mice survived five days. Approximately five times fewer MRSA were collected from the peritoneal fluid of the tamoxifen-treated mice, as compared to control mice. The study was published in the journal Nature Communications.
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