Antifungal activity of tamoxifen: in vitro and in vivo activities and mechanistic characterization.
Tamoxifen (TAM), an estrogen receptor antagonist used primarily to treat breast cancer, has well-recognized antifungal properties, but the activity of TAM has not been fully characterized using standardized (i.e., CLSI) in vitro susceptibility testing, nor has it been demonstrated in an in vivo model of fungal infection. In addition, its mechanism of action remains to be clearly defined at the molecular level. Here, we report that TAM displays in vitro activity (MIC, 8 to 64 microg/ml) against pathogenic yeasts (Candida albicans, other Candida spp., and Cryptococcus neoformans). In vivo, 200 mg/kg of body weight per day TAM reduced kidney fungal burden (-1.5 log(10) CFU per g tissue; P = 0.008) in a murine model of disseminated candidiasis. TAM is a known inhibitor of mammalian calmodulin, and TAM-treated yeast show phenotypes consistent with decreased calmodulin function, including lysis, decreased new bud formation, disrupted actin polarization, and decreased germ tube formation. The overexpression of calmodulin suppresses TAM toxicity, hypofunctional calmodulin mutants are hypersensitive to TAM, and TAM interferes with the interaction between Myo2p and calmodulin, suggesting that TAM targets calmodulin as part of its mechanism of action. Taken together, these experiments indicate that the further study of compounds related to TAM as antifungal agents is warranted.
Dolan
Kristy
K
Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Montgomery
Sara
S
Buchheit
Bradley
B
Didone
Louis
L
Wellington
Melanie
M
Krysan
Damian J
DJ
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002147:Calmodulin / Q000378:metabolism; D002175:Candida / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D002996:Clomiphene / Q000494:pharmacology; D003455:Cryptococcus neoformans / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008856:Microscopy, Fluorescence; D013629:Tamoxifen / Q000494:pharmacology*
D000935:Antifungal Agents; D002147:Calmodulin; D013629:Tamoxifen; D002996:Clomiphene