Tamoxifen as a possible treatment

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Calmodulin antagonists, including
tamoxifen, modulate C. albicans
virulence properties and phagocyte
responses
J. M. Tabroff, K. Koselny, L. P. DiDone, D. J. Krysan, M.
Wellington; University of Rochester, Rochester, NY
The estrogen receptor antagonist tamoxifen (TAM) has significant
anti-Candida activity in vitro and in a mouse model of
systemic candidiasis. While exploring the mechanism of TAM
action in C. albicans, we found that several important virulence
properties are disrupted by TAM treatment. In S. cerevisiae,
TAM disrupts interactions between calmodulin (CaM) and its
binding partners. Therefore, we investigated the effect of TAM
on CaM in C. albicans. Increased extracellular calcium suppressed
TAM toxicity in C. albicans, indicating that TAM targets
a calcium dependent pathway. Furthermore, TAM interferes
with actin localization, cell cycle progression, and polarized
growth in C. albicans. Taken together, these data are consistent
with CaM as the target of TAM action. CaM is particularly
interesting as an antifungal target because there are significant
structural differences between yeast and mammalian CaM.
CaM regulates a wide variety of metabolic processes, including
several associated with virulence. Therefore, we investigated
whether TAM affects C. albicans virulence properties. Treatment
with sub-lethal levels of TAM significantly decreased
germ tube formation, with approximately 20% of TAM-treated
yeast forming germ tubes compared to 80% of controls. Furthermore,
TAM-treatment alters the cell wall; surface exposure
of 1,3-β-glucan is significantly increased in yeast grown in
the presence of TAM. Thus, TAM treatment may be able to
modulate the virulence of C. albicans. Next, we investigated
phagocyte responses to TAM-treated yeast. Using J774 murine
macrophages, we observed a significant increase in phagocyte
binding to TAM-treated yeast (53% of phagocytes bound
control yeast versus 75% with TAM-treated yeast). A similar
increase in phagocytosis was observed. Thus, TAM treatment
of yeast results in enhanced phagocyte responses, which may
improve clearance of the organism. Finally, we investigated
the effect of other CaM antagonists on C. albicans. We found
that both the TAM analog toremifene and an unrelated CaM
antagonist, prochlorperazine, interfered with germ tube formation,
induced surface exposure of 1,3-β-glucan, and enhanced
phagocyte binding. Thus, the ability to modulate these C.
albicans virulence properties appears to be related to CaM antagonism.
These data suggest that CaM antagonists may be an
important new category of antifungal therapy that can modulate
C. albicans virulence and enhance the host response.