Antileishmanial and Antitrypanosomal Activities of the 8-Aminoquinoline Tafenoquine

Yardley, Vanessa; Gamarro, Francisco; Croft, Simon L.

doi:10.1128/aac.00985-10

Cited by 43 publications

(20 citation statements)

References 22 publications

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“…This has also been the case of leishmanicidal drugs such as sitamaquine and tafenoquine . Besides other targets, the mechanism of action of these drugs in Leishmania is related to mitochondrial disorders and their consequences . In the studies described here, we also confirm that the leishmanicidal effect of AMQ is related to mitochondrial dysfunction.…”

Section: Discussionsupporting

confidence: 83%

“…Many antimalarial compounds are based on the usage of quinoline nucleus such as 4‐aminoquinolines, aryl‐aminoquinoline alcohols and 8‐aminoquinolines . This has also been the case of leishmanicidal drugs such as sitamaquine and tafenoquine . Besides other targets, the mechanism of action of these drugs in Leishmania is related to mitochondrial disorders and their consequences .…”

Section: Discussionmentioning

confidence: 99%

“…Some events, including the aforementioned ones, associated with the externalization of the membrane associated phosphatidyl serine and fragmentation of the nuclear DNA are indicated as apoptosis like in protozoan Leishmania . Some drugs, including the 8‐aminoquinolines sitamaquine and tafenoquine, have their leishmanicidal effect associated with an apoptosis‐like event . Further studies are necessary to clarify whether the mode action of AMQ‐j compound is related to apoptosis or another death of Leishmania parasite.…”

Section: Discussionmentioning

confidence: 99%

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4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents

et al. 2015

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The leishmanicidal activity of a series of 4-aminoquinoline (AMQ) derivatives was assayed against Leishmania amazonensis. This activity against the intracellular parasite was found stronger than for L. amazonensis promastigotes. Neither compound was cytotoxic against macrophages. The compound AMQ-j, which exhibited a strong activity against promastigotes and amastigotes of L. amazonensis (IC50 values of 5.9 and 2.4 μg/mL, respectively) and similar leishmanicidal activity to reference drugs, was chosen for studies regarding its possible mechanism of action toward parasite death. The results showed that the compound AMQ-j induced depolarization of the mitochondrial membrane potential in promastigotes and in L. amazonensis-infected macrophages, but not in uninfected macrophages. Furthermore, the depolarization of the mitochondrial membrane potential was dose dependent in infected macrophages. We have established that promastigotes and L. amazonensis-infected macrophages treated with AMQ-j were submitted to oxidative stress. This is in line with the increase in the level of reactive oxygen species (ROS). Leishmania amazonensis-infected macrophages treated with AMQ-j did not show a significant increase in the production of nitric oxide. Our results indicate the effective and selective action of AMQ-j against L. amazonensis, and its mechanism of action appears to be mediated by mitochondrial dysfunction associated with ROS production.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents

et al. 2015

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“…Bray in 1969, and the 1S strain from Sudan, first described by Stauber in 1966 , have been adapted to the in vivo situation in mice and Syrian hamsters, and have ever since become reference laboratory strains to study visceral leishmaniasis. L. donovani strains from the Indian continent, such as the DD8, AG83 and GE1F8R strains have been described in mice and hamsters . Recently, a Nepalese clinical isolate L. donovani strain (BPK282) was fully sequenced and annotated .…”

Section: Introductionmentioning

confidence: 99%

In vivo characterization of two additional Leishmania donovani strains using the murine and hamster model

Kauffmann

Dumetz

Hendrickx

et al. 2016

Parasite Immunology

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Leishmania donovani is a protozoan parasite causing the neglected tropical disease visceral leishmaniasis. One difficulty to study the immunopathology upon L. donovani infection is the limited adaptability of the strains to experimental mammalian hosts. Our knowledge about L. donovani infections relies on a restricted number of East African strains (LV9, 1S). Isolated from patients in the 1960s, these strains were described extensively in mice and Syrian hamsters and have consequently become 'reference' laboratory strains. L. donovani strains from the Indian continent display distinct clinical features compared to East African strains. Some reports describing the in vivo immunopathology of strains from the Indian continent exist. This study comprises a comprehensive immunopathological characterization upon infection with two additional strains, the Ethiopian L. donovani L82 strain and the Nepalese L. donovani BPK282 strain in both Syrian hamsters and C57BL/6 mice. Parameters that include parasitaemia levels, weight loss, hepatosplenomegaly and alterations in cellular composition of the spleen and liver, showed that the L82 strain generated an overall more virulent infection compared to the BPK282 strain. Altogether, both L. donovani strains are suitable and interesting for subsequent in vivo investigation of visceral leishmaniasis in the Syrian hamster and the C57BL/6 mouse model.

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“…Tafenoquine could be further used for the treatment of trypanosoma brucei [28, 29] and leishmania [29-33] infection. Most recently, tafenoquine has been shown to trigger eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane [34].…”

Section: Introductionmentioning

confidence: 99%

Effects of Antimalarial Tafenoquine on Blood Platelet Activity and Survival

Cao¹,

Bissinger²,

Umbach³

et al. 2017

Cell Physiol Biochem

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Background/Aims: The 8-aminoquinoline tafenoquine has been shown to be effective against Plasmodia, Leishmania and Trypanosoma. The substance is at least in part effective by triggering apoptosis of the parasites. Moreover, tafenoquine has been shown to trigger eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. The effect of tafenoquine on eryptosis is in part due to stimulation of Ca²⁺ entry and oxidative stress. Ca²⁺ entry is a critical event in the activation of blood platelets by thrombin and collagen related peptide (CRP). The present study explored, whether tafenoquine influences Ca²⁺ entry, activation and apoptosis of blood platelets. Methods: Platelets isolated from wild-type mice were exposed for 30 minutes to tafenoquine (2.5 µg/ml) without or with an additional treatment with thrombin (0.01 U/ml) or CRP (2 µg/ml or 5 µg/ml). Flow cytometry was employed to estimate cytosolic Ca²⁺-activity ([Ca²⁺]_i) from Fluo-3 fluorescence, platelet degranulation from P-selectin abundance, integrin activation from α_IIbβ₃ integrin abundance, phosphatidylserine abundance from annexin-V-binding, relative platelet volume from forward scatter, reactive oxygen species (ROS) from DCF fluorescence, caspase 3 activity with an active caspase-3 Staining kit, and aggregation utilizing staining with CD9-APC and CD9-PE. Results: Both, thrombin (0.01 U/ml) and CRP (2 µg/ml or 5 µg/ml), significantly increased [Ca²⁺]_i, P-selectin abundance, active α_IIbβ₃ integrin, and annexin-V-binding, and both significantly decreased platelet volume, activated caspase 3 and stimulated aggregation. Administration of tafenoquine (2.5 µg/ml, 30 min) significantly decreased [Ca²⁺]_i both, in the absence and presence of thrombin and CRP. Tafenoquine significantly blunted the effect of thrombin and CRP on [Ca²⁺]_i, P-selectin abundance, and active α_IIbβ₃ integrin, but significantly increased ROS and annexin-V-binding, significantly augmented the effect of thrombin on caspase 3 activity and platelet volume and significantly enhanced platelet aggregation. Conclusions: Tafenoquine counteracts thrombin and CRP induced increase of cytosolic Ca²⁺ activity and platelet activation, but enhances platelet apoptosis and platelet aggregation.

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Antileishmanial and Antitrypanosomal Activities of the 8-Aminoquinoline Tafenoquine

Cited by 43 publications

References 22 publications

4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents

4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents

In vivo characterization of two additional Leishmania donovani strains using the murine and hamster model

Effects of Antimalarial Tafenoquine on Blood Platelet Activity and Survival

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