Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization
Open accessAbstract
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.
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Tamoxifen displayed potent anti-cryptococcal activity in vitro and in a mouse model of disseminated cryptococcosis.
“Similarly, tamoxifen, an oestrogen receptor modulator that is used to treat and prevent breast cancer and osteoporosis, also displayed potent anti-cryptococcal activity in vitro106 and in a mouse model of disseminated cryptococcosis107.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [106]
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Self-citation
- Authors
- Dolan, K., Montgomery, S., Buchheit, B., DiDone, L., Wellington, M., & Krysan, D. J.
- Affiliations
- Departments of Pediatrics
- University of Rochester Medicine (US)
- Corresponding author
- Krysan, Damian J.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2009-08
- Volume
- 53
- Issue
- 8
- Pages
- 3337-3346
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC2715577
- OpenAlex
- W2148427024
- Cited by
- 112
- References
- 52
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 11 · 2022: 9 · 2021: 18 · 2020: 8 · 2019: 12 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 5 · 2014: 9 · 2013: 4 · 2012: 4
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ai075033-03)
- National Institute of Allergy and Infectious Diseases (R01 AI075033, 1R01AI075033)
- National Center for Research Resources (ULI RR02160)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- tamoxifen, antifungal activity, calmodulin inhibition, Candida albicans, Cryptococcus neoformans, systemic candidiasis, germ tube formation, actin polarization, Myo2p, calmodulin mutants, mechanism of action, in vitro susceptibility testing
- MeSH terms
- Animals, Antifungal Agents, Calmodulin, Candida, Candidiasis, Clomiphene, Cryptococcus neoformans, Kidney, Male, Mice, Inbred BALB C, Microbial Sensitivity Tests, Microscopy, Fluorescence, Tamoxifen, Mice
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