Tamoxifen activity against Plasmodium in vitro and in mice.
Ada Weinstock, Julio Gallego-Delgado, Cláudia Gomes, Julian Sherman, Cyrus Nikain, Sandra Gonzalez, Edward Fisher, Ana Rodriguez
Author Information
Ada Weinstock: Departments of Medicine (Cardiology) and Cell Biology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, NY, 10016, USA.
Julio Gallego-Delgado: Department of Biological Sciences, Lehman College, City University of New York, Bronx, New York, NY, 10468, USA. julio.gallegodelgado@lehman.cuny.edu. ORCID
Cláudia Gomes: Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.
Julian Sherman: Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.
Cyrus Nikain: Departments of Medicine (Cardiology) and Cell Biology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, NY, 10016, USA.
Sandra Gonzalez: Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.
Edward Fisher: Departments of Medicine (Cardiology) and Cell Biology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, NY, 10016, USA.
Ana Rodriguez: Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA. ORCID
BACKGROUND: Tamoxifen is an oestrogen receptor modulator that is widely used for the treatment of early stage breast cancer and reduction of recurrences. Tamoxifen is also used as a powerful research tool for controlling gene expression in the context of the Cre/loxP site-specific recombination system in conditional mutant mice. METHODS: To determine whether the administration of tamoxifen affects Plasmodium growth and/or disease outcome in malaria, in vitro studies assessing the effect of tamoxifen and its active metabolite 4-hydroxytamoxifen on Plasmodium falciparum blood stages were performed. Tamoxifen effects were also evaluated in vivo treating C57/B6 mice infected with Plasmodium berghei (ANKA strain), which is the standard animal model for the study of cerebral malaria. RESULTS: Tamoxifen and its active metabolite, 4-hydroxytamoxifen, show activity in vitro against P. falciparum (16.7 to 5.8 µM IC50, respectively). This activity was also confirmed in tamoxifen-treated mice infected with P. berghei, which show lower levels of parasitaemia and do not develop signs of cerebral malaria, compared to control mice. Mice treated with tamoxifen for 1 week and left untreated for an additional week before infection showed similar parasitaemia levels and signs of cerebral malaria as control untreated mice. CONCLUSIONS: Tamoxifen and its active metabolite, 4-hydroxytamoxifen, have significant activity against the human parasite P. falciparum in vitro and the rodent parasite P. berghei in vivo. This activity may be useful for prevention of malaria in patients taking this drug chronically, but also represents a major problem for scientists using the conditional mutagenic Cre/LoxP system in the setting of rodent malaria. Allowing mice to clear tamoxifen before starting a Plasmodium infection allows the use the Cre/LoxP conditional mutagenic system to investigate gene function in specific tissues.
