A Novel Organotellurium Compound (RT-01) as a New Antileishmanial Agent
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Leishmaniasis is a neglected disease and endemic in developing countries. A lack of adequate and definitive chemotherapeutic agents to fight against this infection has led to the investigation of numerous compounds. The aim of this study was to investigate the effect of RT-01, an organotellurane compound presenting biological activities, in 2 experimental systems against Leishmania amazonensis. The in vitro system consisted of promastigotes and amastigotes forms of the parasite, and the in vivo system consisted of L. amazonensis infected BALB/c mice, an extremely susceptible mouse strain. The compound proved to be toxic against promastigotes and amastigotes. The study also showed that treatment with RT-01 produces an effect similar to that treatment with the reference antimonial drug, Glucantime, in L. amazonensis infected mice. The best results were obtained following RT-01 intralesional administration (720 ㎍/kg/day); mice showed significant delay in the development of cutaneous lesions and decreased numbers of parasites obtained from the lesions. Significant differences in tissue pathology consisted mainly of no expressive accumulation of inflammatory cells and wellpreserved structures in the skin tissue of RT-01-treated mice compared with expressive infiltration of infected cells replacing the skin tissue in lesions of untreated mice. These findings highlight the fact that the apparent potency of organotellurane compounds, together with their relatively simple structure, may represent a new avenue for the development of novel drugs to combat parasitic diseases.
Abstract
Leishmaniasis is a neglected disease and endemic in developing countries. A lack of adequate and definitive chemotherapeutic agents to fight against this infection has led to the investigation of numerous compounds. The aim of this study was to investigate the effect of RT-01, an organotellurane compound presenting biological activities, in 2 experimental systems against Leishmania amazonensis. The in vitro system consisted of promastigotes and amastigotes forms of the parasite, and the in vivo system consisted of L. amazonensis infected BALB/c mice, an extremely susceptible mouse strain. The compound proved to be toxic against promastigotes and amastigotes. The study also showed that treatment with RT-01 produces an effect similar to that treatment with the reference antimonial drug, Glucantime, in L. amazonensis infected mice. The best results were obtained following RT-01 intralesional administration (720 ㎍/kg/day); mice showed significant delay in the development of cutaneous lesions and decreased numbers of parasites obtained from the lesions. Significant differences in tissue pathology consisted mainly of no expressive accumulation of inflammatory cells and wellpreserved structures in the skin tissue of RT-01-treated mice compared with expressive infiltration of infected cells replacing the skin tissue in lesions of untreated mice. These findings highlight the fact that the apparent potency of organotellurane compounds, together with their relatively simple structure, may represent a new avenue for the development of novel drugs to combat parasitic diseases.
참고문헌 (30)
- Murray HW, "Advances in leishmaniasis", Lancet, 366, pp.1561~1577 (2005)
- Grimaldi GJ, "Leishmaniasis of the new world: current concepts and implications for future research", Clin Microbiol Rev, 6, pp.230~250 (1993)
- Desjeux P, "Leishmaniasis: current situation and new perspectives", Comp Immunol Microbiol Infect Dis, 27, pp.305~318 (2004)
- Mishra, JA, "Chemotherapy of leishmaniasis: past, present and future", Cur Med Chem, 14, pp.1153~1169 (2007)
- Nogueira CW, "Organoselenium and organotellurium compounds: toxicology and pharmacology", Chem Rev, 104, pp.6255~6285 (2004)
- Chasteen TG, "Biomethylation of selenium and tellurium: microorganisms and plants", Chem Rev, 103, pp.1~25 (2003)
- Cunha RL, "Tellurium-based cysteine protease inhibitors:evaluation of novel organotellurium (IV) compounds asinhibitors of human cathepsin B", Bioorg Med Chem Lett, 15, pp.755~760 (2005)
- Abondanza TS, "Bcl-2 expression and apoptosis induction in human HL60 leukaemic cells treated with a novel organotellurium (IV) compound RT-04", Food Chem Toxicol, 46, pp.2540~2545 (2008)
- Sredni B, "A new immunomodulating compound (AS-101) with potential therapeutic application", Nature, 330, pp.173~176 (1987)
- Wieslander E, "Antioxidative properties of organotellurium compounds in cell systems", Biochem Pharmacol, 55, pp.573~584 (1998)
- Garberg P, "Binding of tellurium to hepatocellular selenoproteins during incubation with inorganic tellurite: consequences for the activity of selenium-dependent glutathione peroxidase", Int J Biochem Cell Biol, 31, pp.291~301 (1999)
- Sailer BL, "Cytometric determination of novel organotellurium compound toxicity in a promyelocytic (HL-60) cell line", Arch Toxicol, 77, pp.30~36 (2003)
- Sredni B, "The protective role of the immunomodulator AS101 against chemotherapy-induced alopecia: studies on human and animal models", Int J Cancer, 65, pp.97~103 (1996)
- Sredni-Kenigsbuch D, "The novel tellurium immunomodulator AS101 inhibits interleukin-10 production and p38 MAPK expression in atopic dermatitis", J Dermatol Sci, 50, pp.232~235 (2008)
- Zukerman-Schpector J, "Benzyltriethylammonium 2,2,2,4-tetrachloro-2,5-dihy- dro-1,2λ5-oxatellurole", Acta Cryst, C56, pp.897~898 (2000)
- Barbieri CL, "Glycosphingolipid antigens from Leishmania (Leishmania) amazonensis amastigotes identified by use of a monoclonal antibody", Infect Immun, 61, pp.2132~2137 (1993)
- Arrais-Silva WW, "Effects of hyperbaric oxygen on Leishmania amazonensis promastigotes and amastigotes", Parasitol Int, 54, pp.1~7 (2005)
- Linares E, "Role of peroxynitrite in macrophage microbicidal mechanisms in vivo revealed by protein nitration and hydroxylation", Free Rad Biol Med, 30, pp.1234~1242 (2001)
- Lemestre JP, "Leishmania spp.: nitric oxide-mediated metabolic inhibition of promastigote and axenically growth amastigote form", Exp Parasitol, 86, pp.58~68 (1997)
- Arrais-Silva WW, "Hyperbaric oxygen therapy reduces the size of Leishmania amazonensisinduced soft tissue lesions in mice", Acta Trop, 98, pp.130~136 (2006)
- Rosenblatt-Bin H, "Antibabesial effect of the immunomodulator AS101 in mice: role of increased production of nitric oxide", Parasite Immunol, 18, pp.297~306 (1996)
- Matlashewski G, "Leishmania infection and virulence", Med Microbiol Immunol, 190, pp.37~42 (2001)
- Mottram JC, "Evidence from disruption of the lmcpb gene array of Leishmania mexicana that cysteine proteinases are virulence factors", Proc Natl Acad Sci, 93, pp.6008~6013 (1996)
- Barral-Netto M, "Different patterns of disease in two inbred mouse strains infected with a clone of Leishmania mexicana amazonensis", Acta Trop, 44, pp.566~11 (1987)
- Macharia JC, "Efficacy of Trypan: a diminazene based drug as antileishmanial agent", Acta Trop, 92, pp.267~272 (2004)
- Frei GM, "Antitumour effects in mycosis fungoides of the immunomodulatory, tellurium-based compound, AS101", Br J Dermatol, 158, pp.578~586 (2008)
- Hayun R, "Novel involvement of the immunomodulator AS101 in IL-10 signaling, via the tyrosine kinase Fer", Ann N Y Acad Sci, 1095, pp.240~250 (2007)
- Kalechman Y, "Delay in the onset of systemic lupus erythematosus following treatment with the immunomodulator AS101: association with IL-10 inhibition and increase in TNF-alpha levels", J Immunol, 159, pp.2658~2667 (1997)
- Sredni B, "Cytokine secretion effected by synergism of the immunomodulator AS101 and the protein kinase C inducer bryostatin", Immunology, 70, pp.473~477 (1990)
- Shohat M, "Cytokine profile of patients with mycosis fungoides and the immunomodulatory effect of AS101", Acta Derm Venereol, 81, pp.255~257 (2001)