Antifungal activity of tamoxifen: In vitro and in vivo activities and mechanistic characterization

Kristy Dolan, Sara Montgomery, Bradley Buchheit, Louis DiDone, Melanie Wellington, Damian J. Krysan

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

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 μg/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 log10 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.

Original languageEnglish (US)
Pages (from-to)3337-3346
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume53
Issue number8
DOIs
StatePublished - Aug 2009
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Antifungal activity of tamoxifen: In vitro and in vivo activities and mechanistic characterization'. Together they form a unique fingerprint.

Cite this