In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii

Gomes, Thaís Cobellis; Júnior, Heitor Franco de Andrade; Lescano, Susana Angélica Zevallos; Amato-Neto, Vicente

doi:10.1590/s0037-86822012000400014

Cited by 17 publications

(13 citation statements)

References 19 publications

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“…The monomeric artemisinins, AS and artemether, have shown good activity against plasmodium parasites and have become the standard of care for malaria. Other intracellular pathogens that infect a broad range of host cells, including viruses, parasites (Toxoplasma), and protozoa (Leishmania), are inhibited by artemisinins (26,27).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

Roy

Kapoor

et al. 2015

Antimicrob Agents Chemother

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dArtemisinin-derived monomers and dimers inhibit human cytomegalovirus (CMV) replication in human foreskin fibroblasts (HFFs). The monomer artesunate (AS) inhibits CMV at micromolar concentrations, while dimers inhibit CMV replication at nanomolar concentrations, without increased toxicity in HFFs. We report on the variable anti-CMV activity of AS compared to the consistent and reproducible CMV inhibition by dimer 606 and ganciclovir (GCV). Investigation of this phenomenon revealed that the anti-CMV activity of AS correlated with HFFs synchronized to the G 0 /G 1 stage of the cell cycle. In contact-inhibited serum-starved HFFs or cells arrested at early/late G 1 with specific checkpoint regulators, AS and dimer 606 efficiently inhibited CMV replication. However, in cycling HFFs, in which CMV replication was productive, virus inhibition by AS was significantly reduced, but inhibition by dimer 606 and GCV was maintained. Cell cycle analysis in noninfected HFFs revealed that AS induced early G 1 arrest, while dimer 606 partially blocked cell cycle progression. In infected HFFs, AS and dimer 606 prevented the progression of cell cycle toward the G 1 /S checkpoint. AS reduced the expression of cyclin-dependent kinases (CDK) 2, 4, and 6 in noninfected cycling HFFs, while the effect of dimer 606 on these CDKs was moderate. Neither compound affected CDK expression in noninfected contact-inhibited HFFs. In CMV-infected cells, AS activity correlated with reduced CDK2 levels. CMV inhibition by AS and dimer 606 also correlated with hypophosphorylation (activity) of the retinoblastoma protein (pRb). AS activity was strongly associated with pRb hypophosphorylation, while its reduced anti-CMV activity was marked by pRb phosphorylation. Roscovitine, a CDK2 inhibitor, antagonized the anti-CMV activities of AS and dimer 606. These data suggest that cell cycle modulation through CDKs and pRb might play a role in the anti-CMV activities of artemisinins. Proteins involved in this modulation may be identified and targeted for CMV inhibition.A rtemisinins, drugs of choice for malaria therapy, inhibit human cytomegalovirus (CMV) replication (1-4). Artesunate (AS) and the parent compound artemisinin inhibit CMV replication in vitro and in vivo. Variable responses to AS in case reports of CMV-infected patients have been attributed to the dosing regimen, duration of therapy, or tissue penetration of AS (5-8). In our effort to improve and uncover the anti-CMV activities of artemisinins, we reported on in vitro highly selective inhibition of CMV replication with artemisinin-derived dimers, significantly more than with their monomeric counterparts, without increasing toxicity in human foreskin fibroblasts (HFFs) (3, 9). Although similar effects on CMV replication were observed between monomers and dimers (timing of CMV inhibition, effects on DNA replication, and virus yield), dimers inhibited CMV at nanomolar concentrations and had a high slope of the dose-response curve, a measure of cooperativity in binding of multiple ligands to linked bi...

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Section: Discussionmentioning

confidence: 99%

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

Roy

Kapoor

et al. 2015

Antimicrob Agents Chemother

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“…[ 1 ] A previous study investigated the efficacy of artesunate (artemisinin derivatives) on the T. gondii and indicated best effect with low IC 50 value compared to other examined drugs such as pentamidine and pyrimethamine. [ 25 ] These findings showed that artemisinin and its derivatives are not only a potent new compound of antimalarial,[ 26 ] but also they are able to control various strains of T. gondii in vitro and in vivo. [ 24 ]…”

Section: Discussionmentioning

confidence: 99%

Apoptotic activity and anti-Toxoplasma effects of artemether on the tachyzoites and experimental infected Vero and J774 cell lines by Toxoplasma gondii

et al. 2016

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Objectives:Drugs used for toxoplasmosis have limited efficacy and also severe side effects. A new drug with good efficacy and limited side effects is need of the hour. We studied the effects of artemether on Toxoplasma gondii in vitro conditions.Materials and Methods:Artemether (methyl-ether-qinghaosu) was tested for tachyzoites, J774, and Vero cell lines infected by T. gondii. For evaluating the effect of drugs on Vero cells infected with T. gondii, we designed two separate experiments; in the first experiment, the Vero cells were infected with tachyzoites and then treated with artemether; while in the second one, the tachyzoites were exposed to artemether and then Vero cells were infected with treated tachyzoites. For evaluating the apoptotic effect of artemether on tachyzoites and infected J774 macrophages cell line with T. gondii, we used flow cytometry method. Inhibitory concentration (IC50) was evaluated by intracellular replication of tachyzoites in Vero cells.Results:IC50 for infected Vero cells with tachyzoites was determined as 49.13 μg/ml. In pretreated tachyzoites with artemether before entering into Vero cells, IC50 was calculated as 13.15 μg/ml. In both experiments, artemether showed a higher inhibitory effect than sulfadiazine (positive control). Artemether even at the highest concentrations only showed low cytotoxicity on Vero and J774 cell lines. Apoptosis in tachyzoites rise with an increasing concentration of artemether.Conclusions:Our findings indicate that artemether is effective to control the tachyzoites of T. gondii in vitro and maybe a good alternative drug for toxoplasmosis.

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“…ART and its derivatives tested for their in vitro efficacy (IC 50 ) against T. gondii and cytotoxicity (TD 50 ) were measured to obtain the selectivity (SI) and/or therapeutic index (TI). Artesunate is proven to have much higher efficacy than current first-line drugs such as cotrimoxazole, pentamidine, pyrimethamine, and trimethoprim [58]. Intraparasitic heme activates ART and its derivatives to form reactive oxygen species (ROS) in the cytoplasm of host cells, which is then delivered across the parasitophorous vacuole membrane (PVM) to reach the tachyzoites within the PVM.…”

Section: Art and Its Derivatives On T Gondiimentioning

confidence: 99%

Artemisinin and its derivatives in treating protozoan infections beyond malaria

Loo

Lam

et al. 2017

Pharmacological Research

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Many parasitic protozoan diseases continue to rank among the world’s greatest global health problems, which are also common among poor populations. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. Artemisinin (ART) and its derivatives are some of the most important classes of antimalarial agents originally derived from Artemisia annua L. However, besides the outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess activities against other parasitic protozoa. In this paper, we reviewed the activities of ART and its derivatives against protozoan parasites in in vitro and in vivo, including Leishmania spp., Trypanosoma spp., Toxoplasma gondii, Neospora caninum, Eimeria tenella, Acanthamoeba castellanii, Naegleria fowleri, Cryptosporidium parvum, Giardia lamblia, and Babesia spp. We concluded that ART and its derivatives may be good alternatives for treating other non-malarial protozoan infections in developing countries, although more studies are necessary before they can be applied clinically.

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In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii

Cited by 17 publications

References 19 publications

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

Apoptotic activity and anti-Toxoplasma effects of artemether on the tachyzoites and experimental infected Vero and J774 cell lines by Toxoplasma gondii

Artemisinin and its derivatives in treating protozoan infections beyond malaria

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