Journal article
Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization
Antimicrobial agents and chemotherapy, Vol.53(8), pp.3337-3346
08/2009
DOI: 10.1128/AAC.01564-08
PMCID: PMC2715577
PMID: 19487443
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 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.
Details
- Title: Subtitle
- Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization
- Creators
- Kristy Dolan - Departments of PediatricsSara Montgomery - Departments of PediatricsBradley Buchheit - Departments of PediatricsLouis DiDone - Departments of PediatricsMelanie Wellington - Departments of PediatricsDamian J Krysan - Departments of Pediatrics
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.53(8), pp.3337-3346
- DOI
- 10.1128/AAC.01564-08
- PMID
- 19487443
- PMCID
- PMC2715577
- NLM abbreviation
- Antimicrob Agents Chemother
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Publisher
- American Society for Microbiology (ASM)
- Language
- English
- Date published
- 08/2009
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984093504302771
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