Multidrug resistance in the protozoan parasite Entamoeba histolytica

Orozco, Esther; López, César; Gómez, Consuelo; Pérez, D.Guillermo; Marchat, Laurence A.; Bañuelos, Cecilia; Delgadillo, Dulce María

doi:10.1016/s1383-5769(02)00041-7

Cited by 49 publications

(26 citation statements)

References 32 publications

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“…The overexpression of Pgps is directly linked to the multiple drug resistance (MDR) phenotype observed in both mammalian tumour cells and the protozoan parasites Entamoeba and Leishmania [51][52][53][54][55]. The presence of Pgps has been documented, though not intensively studied in T. vaginalis [56].…”

Section: Multiple Drug Resistancementioning

confidence: 99%

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

et al. 2003

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Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved, effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and cross-resistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

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Section: Multiple Drug Resistancementioning

confidence: 99%

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

et al. 2003

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“…MDR is associated with the overexpression of a 170-kDa membrane molecule known as P-glycoprotein (PGP), an energy-dependent pump that extrudes drugs from the cells (5,6). In E. histolytica, MDR phenotype is given mainly by overexpression of the EhPgp1 and EhPgp5 genes, which are finely regulated by transcriptional factors (7)(8)(9). Although EhPgp1 is constitutively expressed in drug-resistant trophozoites of clone C2, EhPgp5 gene is overexpressed only when C2 cells are grown in a high emetine concentration (10,11).…”

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confidence: 99%

EhPgp5 mRNA Stability Is a Regulatory Event in theEntamoeba histolytica Multidrug Resistance Phenotype

López-Camarillo¹,

Luna-Arias²,

Marchat³

et al. 2003

Journal of Biological Chemistry

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The multidrug resistance (MDR) phenotype inEntamoeba histolytica, the protozoan parasite responsible for human amoebiasis, presents the multidrug resistance (MDR) 1 phenotype (1) described first in mammalian cells (2) and then in several protozoan parasites (3, 4). MDR is associated with the overexpression of a 170-kDa membrane molecule known as P-glycoprotein (PGP), an energy-dependent pump that extrudes drugs from the cells (5, 6). In E. histolytica, MDR phenotype is given mainly by overexpression of the EhPgp1 and EhPgp5 genes, which are finely regulated by transcriptional factors (7-9). Although EhPgp1 is constitutively expressed in drug-resistant trophozoites of clone C2, EhPgp5 gene is overexpressed only when C2 cells are grown in a high emetine concentration (10, 11). Both genes are also amplified in the presence of a high drug concentration (12).Transcriptional regulation of eukaryotic mdr genes has been considered as the major control point for PGP synthesis, although gene amplification mechanisms also participate in this event (12, 13). Moreover, there is growing evidence of pivotal post-transcriptional (14 -17) and post-translational (18 -20) regulation of the PGP expression. On the other hand, mRNA stability has recently emerged as a critical control step in determining cellular stationary mRNA levels. The abundance of a particular mRNA can fluctuate many folds due to alterations in mRNA stability without any change in the transcription rate (21). The mRNA half-life is determined by a complex set of protein interactions at the 3Ј-untranslated region (3Ј-UTR) depending on conserved cis-element sequences and secondary structures (for review, see Ref. 22). The 3Ј-UTR also contains consensus sequence elements that mediate mRNA nuclear export, cytoplasmic localization, translation efficacy, and polyadenylation control (23, 24). The pre-mRNAs are polyadenylated in a reaction involving 3Ј endonucleolytic cleavage followed by poly(A) tail synthesis (25). Poly(A) tail is also a modulator of mRNA stability and translation (26,27). Strict control of poly(A) tail length is achieved by the concerted interplay of key factors, including poly(A) polymerase, deadenylases, and poly(A)-binding protein activities (25).Several reports have addressed the importance of mRNA stability on the mdr genes expression regulation. Pgp1, Pgp2, and Pgp3 mRNAs have a higher half-life in rat tumor cells than in normal cells (15), whereas rat MDR hepatocytes in culture present a higher amount of PGP2 protein due to a post-transcriptional mechanism controlling mRNA stability (14). Human MDR1 mRNA has a half-life of 30 min, which is prolonged to more than 20 h upon treatment with cycloheximide, suggesting that protein synthesis inhibition may influence the stability of certain mRNAs (16,17). However, molecular mechanisms controlling mdr mRNA stability remains to be elucidated.In E. histolytica, mRNA stability mechanisms have not been studied yet. The presence of higher levels of EhPGP5 protein in the multidrug-resistant trophozoites of c...

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“…The present recommendations are to combine this drug with some luminal amoebicidal like paromycin or diloxanide furoate. Though metronidazole is effective in treating the amoebiasis but it resulted in failure due to development of resistance by E. histolytica against it (Orozco, 2002;Gonzales, 2009).…”

Section: Discussionmentioning

confidence: 99%

Comparison of allopathic and herbal medicine for the treatment of Entamoeba histolytica: A double blind clinical trial

Siddiqui¹,

Usmanghani²

2015

J. Med. Plants Res.

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This parallel, randomized, double blind clinical trial was designed to compare allopathic drugs [a combination of metronidazole + diloxanide furoate (MDF)] with Endemali (herbal product) for therapeutic cure rate and side effects in order to find out the most suitable drug for this killer disease. This double blind randomized clinical trial was conducted in two areas of Karachi, Pakistan after approval from ethical committee of Hamdard University. All those confirmed for Entamoeba histolytica were included in the study. One hundred and seventy one patients selected for the study were randomly allocated to two arms of 86 and 85 for allopathic and herbal treatment, respectively. However 78 in allopathic and 75 in herbal group completed the study. Main outcome variable was treatment success or failure. Secondary outcome measures included side effects and association with age and sex. No significant difference was observed in the socio economic and demographic variables at the baseline. No significant difference was found between the cure rate of MDF and Endemali; hence both drugs were equally effective in treating amoebiasis. Significant differences were reported for the side effects observed among the two groups and the price. The failure rate for the two drugs was 28.7%. It is concluded that both Endemali and MDF are equally effective in treating amoebiasis. However, Endemali has fewer side effects than MDF. New drugs need to be researched for the treatment of E. histolytica because of high failure rate of the two drugs against this killer organism.

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Multidrug resistance in the protozoan parasite Entamoeba histolytica

Cited by 49 publications

References 32 publications

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

EhPgp5 mRNA Stability Is a Regulatory Event in theEntamoeba histolytica Multidrug Resistance Phenotype

Comparison of allopathic and herbal medicine for the treatment of Entamoeba histolytica: A double blind clinical trial

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