The antileishmanial drug miltefosine (Impavido ® ) causes oxidation of DNA bases, apoptosis, and necrosis in mammalian cells

Branco, Patrícia Valéria Castelo; Soares, Rossy-Eric Pereira; Jesus, Luís Cláudio Lima de; Moreira, Vanessa; Alves, Hugo José; Belfort, Marta Regina de Castro; Silva, Vera Lucia Maciel; Pereira, Silma Regina Ferreira

doi:10.1016/j.mrgentox.2016.06.007

Cited by 10 publications

(13 citation statements)

References 36 publications

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“…The results obtained for the reference drug, meglumine antimonate, were included in all cases for comparison. Biological data evidenced that half of the screened compounds (compounds 8,9,10,11,13,15,17,18,20,21,24,26,29,33,35,37,38,42,43,44,45,46, 47, and 48) showed high levels of bioactivity against L. infantum, presenting greater potency than the reference drug, meglumine antimonate, against both forms (IC 50 s, 18.0 M for promastigotes and 24.2 M for amastigotes).…”

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confidence: 99%

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Martín‐Montes

Plano

Martín‐Escolano

et al. 2017

Antimicrob Agents Chemother

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The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.KEYWORDS Leishmania, selenium, superoxide dismutase, glucose metabolism L eishmaniasis, caused by the intracellular protozoan Leishmania, is transmitted by the bite of phlebotomine sand flies and is endemic in 98 countries, with over 350 million people being at risk (1). Environmental, demographic, and human behavioral factors and coinfections contribute to the changing epidemiology of the disease and to its recent worldwide spread. Clinical manifestations are divided into visceral leishmaniasis (VL; or kala-azar) (2) and the forms cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (ML). CL remains the most common form of leishmaniasis both in general and in international travelers (3-5).The drugs available for the treatment of VL and severe CL include pentavalent antimonials (SbV), deoxycholate, amphotericin B (AMB), and miltefosine (MIL), all of which have high levels of toxicity and/or require long-duration treatment schedules (5, 6). Moreover, with the exception of MIL, all these drugs must be administered by the parenteral route (7).In the last decade, resistance to SbV has increased mainly due to low rates of compliance with the treatment schedule. In areas where the parasites are resistant to

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confidence: 99%

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Martín‐Montes

Plano

Martín‐Escolano

et al. 2017

Antimicrob Agents Chemother

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“…Firstly, considering that miltefosine causes genomic instability and mutations in uninfected Swiss mice (Castelo-Branco et al, 2016), the ability of ascorbic acid to protect the DNA was assessed by comet assay and micronucleus test. For that, Swiss mice received single dose of both compounds in simultaneous, pre and post treatments.…”

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confidence: 99%

“…Toxicogenetic tests were performed by comet and micronucleus assays, and the parasite burden was determined in lymph node and spleen by limiting dilution. Moreover, considering previous data that showed miltefosine causes oxidation of DNA bases (Castelo-Branco et al, 2016), enzyme superoxide dismutase activity was measured in serum. Briefly, on 14th and 28th days after treatments, peripheral blood was obtained from the tail of each animal to perform comet assay.…”

Section: Methodsmentioning

confidence: 99%

“…Assays with miltefosine were conducted under different treatment conditions. For this purpose, animals were divided into two groups: 1) uninfected Swiss mice receiving a single dose (70 mg/kg) of miltefosine (Chemical Cayman Company, MI, USA, batch 0463792-1) as previously described (Castelo Branco et al, 2016); 2) infected Balb/c mice which received miltefosine (Impavido ® ) at 2.5 mg/kg for 28 days, as recommended by the World Health Organization for human treatment; and another group that received 5.0 mg/kg for 14 days. In both assays, the drug was dissolved in distilled water and administered via gavage.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, our laboratory demonstrated the ability of this antileishmanial to cause apoptosis, necrosis and genomic lesions with oxidation of purine bases in mammalian cells (Castelo Branco et al, 2016). Oxidation of bases occurs due to the oxidative stress caused by the imbalance between the Reactive Oxygen Species (ROS) and the antioxidant defense system, with a predominance of ROS (Vasconcelos et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Ascorbic acid reduces the genetic damage caused by miltefosine (hexadecylphosphocholine) in animals infected by Leishmania (Leishamnia) infantum without decreasing its antileishmanial activity

Castelo-Branco

Alves

Pontes

et al. 2019

International Journal for Parasitology: Drugs and Drug Resistan

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Leishamaniasis is a neglected disease caused by over 20 Leishmania species, occurring in more than a hundred countries. Miltefosine (hexadecylphosphocholine) is the single oral drug used in treatment for leshmaniases, including cases of infections resistant to pentavalent antimony. Our group has recently demonstrated the ability of miltefosine to cause genomic lesions by DNA oxidation. Acknowledging that antioxidant compounds can potentially modulate Reactive Oxygen Species (ROS), our study verified whether ascorbic acid reduces the genotoxic and mutagenic effects caused by miltefosine, and whether it interferes with drug efficacy. For this purpose, uninfected Swiss mice received simultaneous (single dose treatment) miltefosine and ascorbic acid (gavage and intraperitoneally), besides pre and post treatments (ascorbic acid 24 h before and after drug administration); furthermore, Balb/c mice infected with Leishmania infantum received miltefosine plus ascorbic acid (repeated doses treatment). We conducted comet assays, micronucleus tests, dosages of superoxide dismutase enzyme and parasitic burden by the limiting dilution assay. We observed that ascorbic acid administered intraperitoneally displayed a protective effect over damage caused by miltefosine. However, this effect was not not observed when the same doses were administered via gavage, possibly due to low serum levels of this antioxidant. Ascorbic acid's protective effect reinforces that miltefosine damages DNA by oxidizing its nitrogenous bases, which is reduced by ascorbic acid due to its ability of protecting genetic material from the action of ROS. Therefore, our results show that this drug is efficient in reducing parasitic burden of L. infantum.

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Synthesis and Evaluation of New 1,2,3‐triazole Alkyl Derivatives and Their Salts Against Breast Cancer Cells

De Paula,

Glanzmann,

Da Costa Nunes

et al. 2024

ChemistrySelect

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Breast cancer is responsible for causing the death of women across various age groups worldwide. Alkylphosphocholines such as miltefosine are attractive for the chemical therapy of this neoplasm, but have disadvantages such as gastrointestinal problems, occasional hepatotoxicity and nephrotoxicity, and potential teratogenicity. In the present study, a series of 1‐alkyl‐1,2,3‐triazoles and organic salts were synthesized, as new non‐classical miltefosine bioisosteres, and biological studies were performed using human cells from the triple‐negative MDA‐MB‐231 breast cancer. The results showed that 1,2,3‐triazolic salts substituted with aliphatic chains of 16 carbons showed antitumor action, with half‐maximum inhibitory concentration values between 3.2 and 6.4 μM. Furthermore, clonogenic assays were conducted to predict the chemosensitivity of the most promising compounds, which supported the findings from the IC50 values, highlighting two main compounds with significant efficacy in reducing clonogenic survival compared to the control group. In conclusion, two 1,2,3‐triazolic salts exhibited promising antitumor effects and warrant further investigation for potential therapeutic use against the disease.

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The antileishmanial drug miltefosine (Impavido ® ) causes oxidation of DNA bases, apoptosis, and necrosis in mammalian cells

Cited by 10 publications

References 36 publications

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Ascorbic acid reduces the genetic damage caused by miltefosine (hexadecylphosphocholine) in animals infected by Leishmania (Leishamnia) infantum without decreasing its antileishmanial activity

Synthesis and Evaluation of New 1,2,3‐triazole Alkyl Derivatives and Their Salts Against Breast Cancer Cells

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