Chloroquine is therapeutic in murine experimental model of paracoccidioidomycosis

Abstract

Chloroquine, due to its basic properties, has been shown to prevent the release of iron from holotransferrin, thereby interfering with normal iron metabolism in a variety of cell types. We have studied the effects of chloroquine on the evolution of experimental paracoccidioidomycosis by evaluating the viable fungal recovery from lung, liver and spleen from infected mice and H(2)O(2), NO production, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-10 levels and transferrin receptor (TfR) expression from uninfected and infected peritoneal macrophages. Chloroquine caused a significant decrease in the viable fungal recovery from all organs tested, during all periods of evaluation. Peritoneal macrophages from chloroquine-treated infected mice showed higher H(2)O(2) production and TfR expression, and decreased levels of NO, endogenous and stimulated-TNF-alpha, IL-6 and IL-10 during the three evaluated periods. However, despite its suppressor effects on the macrophage function, the chloroquine therapeutic effect upon murine paracoccidioidomycosis was probably due to its effect on iron metabolism, blocking iron uptake by cells, and consequently restricting iron to fungus growth and survival.

Cell Wall Perturbation Sensitizes Fungi to the Antimalarial Drug Chloroquine

“…Furthermore, concentrations as low as 32 M CQ are known to cause growth inhibition in human cell lines (47). However, whereas the concentrations used in this study were appropriate in vitro, a mode of antifungal CQ action that relies on iron deprivation due to external alkalinization (12,14,15) could be expected to be exacerbated markedly in vivo. Thus, fungal pathogens would likely be more susceptible to caspofungin-dependent CQ uptake during in vivo infection.…”

“…However, a mode of antifungal CQ action based on alkalinization of the host environment and iron deprivation has been proposed (12,14,15). Pathogens such as C. albicans themselves can actively alkalinize their environments (42), and this action could exacerbate CQ action.…”

“…In addition to this antimalarial activity, CQ has been shown to have anti-inflammatory properties and has been used widely in the treatment of arthritis (11). There have also been reports of CQ activity against fungal pathogens (12)(13)(14)(15). The mechanism is thought to involve alkalinization of the host environment of the fungi, with associated iron deprivation in some cases.…”

Fungal adaptation to the mammalian host: it is a new world, after all

“…In each of these cases, chloroquine’s alkalinizing activity was essential for restriction of fungal growth (47,48). Most recently, the story has come full circle, as chloroquine restricts intracellular growth of P. brasiliensis in an iron-dependent manner and is therapeutic in a mouse model for paracoccidoidomycosis (49,50). Chloroquine has thus emerged as a drug with broad anti-fungal capacity that acts by altering abiotic parameters of the host environment.…”

Signaling of Chloroquine-Induced Stress in the Yeast Saccharomyces cerevisiae Requires the Hog1 and Slt2 Mitogen-Activated Protein Kinase Pathways

“…There is evidence that CQ may affect multiple cellular processes, including activation of apoptosis, by inhibiting autophagic protein degradation (1)(2)(3) and cellular stress response pathways (4), antigen presentation (5), and oxidative stress responses (6). Apart from its antimalarial activity, CQ has emerged as a potential anticancer agent (2) and antifungal agent (7)(8)(9)(10), and it is also known to possess antiviral activity (11,12). The cytotoxic effects of CQ have been demonstrated for tumor cells derived from different types of human cancers (2,13,14).…”