Tamoxifen is effective in the treatment of Leishmania amazonensis infections in mice

25 Jun 2008

Marcia Triunfol

Source: PLoS Neglected Tropical Diseases (see original article or PDF)

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Citation: Miguel DC, Yokoyama-Yasunaka JKU, Uliana SRB (2008) Tamoxifen is effective in the treatment of Leishmania amazonensis infections in mice. PLoS Negl Trop Dis 2(6): e249.

Tamoxifen is a drug that is widely used for treating oestrogen receptor positive (ER+) breast cancer. In patients with ER+ breast cancer, the drug acts by binding to oestrogen receptors that are required for cancer cells to grow. The binding prevents cancer cells from passing the G0 or G1 phases of the cell cycle. The drug is also used to prevent breast cancer in women at high risk of having the disease or a recurrence.

Leishmaniasis is treated with antimonials and amphotericin B. However, these drugs have several side-effects and, for diffuse cutaneous leishmaniasis (DLC) a serious disease characterized by multiple skin lesions, there is no effective treatment.

In the search for an effective drug to treat DLC, in 2006 a group in Brazil tested the chemotherapeutic and chemopreventive drug tamoxifen for a possible effect against Leishmania amazonensis (1), which is one of the main species that causes DLC in South America. The in vitro study done at the time showed that tamoxifen indeed possesses leishmanicidal activity and that a concentration of 10uM of tamoxifen has the potential to inhibit 50% of L. amazonensis viability and growth.

In the present study, the same group went one step further and tested the effects of tamoxifen against leishmaniasis in BALB/c mice infected with L. amazonensis.

Treatment with 20 mg/kg/day of intraperitoneal tamoxifen was initiated five weeks post-infection and continued for 15 days. On week seven after infection, and therefore when treatment with tamoxifen was finished, tamoxifen-treated mice not only showed a delay in the appearance and development of ulcers but also their ulcers were significantly less thick than those observed in the control group. Additionally, treated animals had a significant lower number of parasites per lesion during the study period and reached a 99.7% reduction by the end of the study. An additional test showed that the remaining parasites in the treated group were no less sensitive to tamoxifen, which indicates that no resistance against the drug had developed.

The study shows evidence of the leishmanicidal action of tamoxifen in infected mice, although the mechanism by which this action occurs is not totally understood. In any case, this action does not seem to be related to oestrogen, as the earlier study had shown (1). Therefore, no gender-dependent response to this drug should be expected.

Tamoxifen has been used for many years and, although its use is associated with serious side-effects, these usually relate to the long-term use of the drug by breast-cancer patients. According to the preliminary data presented in this study, no long-term use would be necessary for treating leishmaniasis, as a significant improvement in infected mice was detected after only a 15-day treatment with tamoxifen.

Tamoxifen may be a better option for treating patients with leishmaniasis. Potentially it would have fewer side-effects – or none at all – and it is the only drug that has shown a satisfactory effect against DCL.

Reference

1. Miguel DC, Yokoyama-Yasunaka JK, Andreoli WK, Mortara RA, Uliana SR (2007). Tamoxifen is effective against Leishmania and induces a rapid alkalinization of parasitophorous vacuoles harbouring Leishmania (Leishmania) amazonensis amastigotes. J Antimicrob Chemother; 60:526-34.

2008, Miguel DC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Source

Title:
Tamoxifen is effective in the treatment of Leishmania amazonensis infections in mice.

Authors:
Miguel DC, Yokoyama-Yasunaka JK, Uliana SR

References:
PLoS Negl Trop Dis 2008: Vol. 2 no. 6, pp. e249

Abstract:
Chemotherapy is still a critical issue in the management of leishmaniasis. Until recently, pentavalent antimonials, amphotericin B or pentamidine compounded the classical arsenal of treatment. All these drugs are toxic and have to be administered by the parenteral route. Tamoxifen has been used as an antiestrogen in the treatment and prevention of breast cancer for many years. Its safety and pharmacological profiles are well established in humans. We have shown that tamoxifen is active as an antileishmanial compound in vitro, and in this paper we analyzed the efficacy of tamoxifen for the treatment of mice infected with Leishmania amazonensis, an etiological agent of localized cutaneous leishmaniasis and the main cause of diffuse cutaneous leishmaniasis in South America.BALB/c mice were infected with L. amazonensis promastigotes. Five weeks post-infection, treatment with 15 daily intraperitoneal injections of 20 mg/kg tamoxifen was administered. Lesion and ulcer sizes were recorded and parasite burden quantified by limiting dilution. A significant decrease in lesion size and ulcer development was noted in mice treated with tamoxifen as compared to control untreated animals. Parasite burden in the inoculation site at the end of treatment was reduced from 10(8.5+/-0.7) in control untreated animals to 10(5.0+/-0.0) in tamoxifen-treated mice. Parasite load was also reduced in the draining lymph nodes. The reduction in parasite number was sustained: 6 weeks after the end of treatment, 10(15.5+/-0.5) parasites were quantified from untreated animals, as opposed to 10(5.1+/-0.1) parasites detected in treated mice.Treatment of BALB/c mice infected with L. amazonensis for 15 days with tamoxifen resulted in significant decrease in lesion size and parasite burden. BALB/c mice infected with L. amazonensis represents a model of extreme susceptibility, and the striking and sustained reduction in the number of parasites in treated animals supports the proposal of further testing of this drug in other models of leishmaniasis.

PMID: 18545685
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