Inhibition of HSP90 in
            <i>Trypanosoma cruzi</i>
            Induces a Stress Response but No Stage Differentiation

Graefe, Sebastian E. B.; Wiesgigl, Martina; Gaworski, Iris; MacDonald, Andrea; Clos, Joachim

doi:10.1128/ec.1.6.936-943.2002

Cited by 75 publications

(51 citation statements)

References 33 publications

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“…In Leishmania donovani, Hsp90 plays a key role in the differentiation of the promastigote stage to the pathogenic mammalian amastigote stage (31). Hsp90 is also implicated in the development and survival of other intracellular parasites, such as Eimeria tenella (53), Toxoplasma gondii (54), and Trypanosoma cruzi (55). Hsp90 was found to be essential in the filarial nematode Brugia pahangi; exposure of B. pahangi to geldanamycin, a specific inhibitor of Hsp90, killed adult worms and microfilariae in vitro (56,57).…”

Section: Discussionmentioning

confidence: 99%

Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases

Debnath

Shahinas

Bryant

et al. 2014

Antimicrob Agents Chemother

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Entamoeba histolytica and Giardia lamblia are anaerobic protozoan parasites that cause amebiasis and giardiasis, two of the most common diarrheal diseases worldwide. Current therapy relies on metronidazole, but resistance has been reported and the drug has significant adverse effects. Therefore, it is critical to search for effective, better-tolerated antiamebic and antigiardial drugs. We synthesized several examples of a recently reported class of Hsp90 inhibitors and evaluated these compounds as potential leads for antiparasitic chemotherapy. Several of these inhibitors showed strong in vitro activity against both E. histolytica and G. lamblia trophozoites. The inhibitors were rescreened to discriminate between amebicidal and giardicidal activity and general cytotoxicity toward a mammalian cell line. No mammalian cytotoxicity was found at >100 M for 48 h for any of the inhibitors. To understand the mechanism of action, a competitive binding assay was performed using the fluorescent ATP analogue bis-ANS (4,4=-dianilino-1,1=-binaphthyl-5,5=-disulfonic acid dipotassium salt) and recombinant E. histolytica Hsp90 preincubated in both the presence and absence of Hsp90 inhibitors. There was significant reduction in fluorescence compared to the level in the control, suggesting that E. histolytica Hsp90 is a selective target. The in vivo efficacy and safety of one Hsp90 inhibitor in a mouse model of amebic colitis and giardiasis was demonstrated by significant inhibition of parasite growth at a single oral dose of 5 mg/kg of body weight/day for 7 days and 10 mg/kg/day for 3 days. Considering the results for in vitro activity and in vivo efficacy, Hsp90 inhibitors represent a promising therapeutic option for amebiasis and giardiasis.

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Section: Discussionmentioning

confidence: 99%

Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases

Debnath

Shahinas

Bryant

et al. 2014

Antimicrob Agents Chemother

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“…The HSP90 protein family comprises evolutionarily conserved abundant cytosolic proteins that have been involved in chaperone function, oncogenic transformation, cell cycle control, and antigen presentation. This family also functions in the structural folding and maintenance of the conformational integrity of various proteins, including several cellular signal transduction proteins (Csemely et al 1998;Byrd et al 1999;Graefe et al 2002;Prodromou and Pearl 2003;Tsutsumi and Neckers 2007;Hao et al 2010). HSP90 is also required for normal spermatogenesis, oogenesis, and embryogenesis in Drosophila spp.…”

Section: Introductionmentioning

confidence: 99%

Characterizing heat shock protein 90 gene of Apolygus lucorum (Meyer-Dür) and its expression in response to different temperature and pesticide stresses

Sun

Sheng

Bai

et al. 2014

Cell Stress and Chaperones

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In this study, we cloned a full-length cDNA of heat shock protein (HSP) gene of Apolygus lucorum (Meyer-Dür) [AlHSP90, KC109781] and investigated its expression in response to temperature and pesticide stresses. The open reading frame (ORF) of AlHSP90 is 2,169 bp in length, encoding a 722 amino acid polypeptide with a predicted molecular weight of 82.99 kDa. Transcriptional and translational expression profiles of AlHSP90 under extreme temperature or pesticide stresses were examined by fluorescent realtime quantitative PCR and Western blot. Results showed that the expression profiles of AlHSP90 protein were in high agreement with those of AlHSP90 RNA and indicated that AlHSP90 was not only an important gene for A. lucorum adults in response to extremely high temperature, but also involved in the resistance or tolerance to cyhalothrin, imidacloprid, chlorpyrifos, and emamectin benzoate, especially for female adults to emamectin benzoate and for male adults to cyhalothrin. Transcriptional results of AlHSP90 also confirmed that AlHSP90 was an important gene involved in the resistance or tolerance to both temperature and pesticide stresses. In addition, our study also revealed that ∼24°C may be the suitable temperature range for A. lucorum survival, which is also confirmed by the results of the expression of AlHSP90, the nymph mortality, and the intrinsic rate of increase (r m ) when A. lucorum is reared at six different temperatures. Therefore, these studies are significant in elucidating the AlHSP90 in response to temperature and pesticide stresses and would provide guidance for A. lucorum management with different pesticides or temperatures in fields.

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“…Hsp90 function is, thus, critical for survival of T. brucei. In other systems, inhibition of Hsp90 function by GA causes proteotoxic stress, which induces expression of various heat shock proteins (Wiesgigi and Clos 2001;Graefe et al 2002;Kamal et al 2004). We found that GA treatment also induces the level of Hsp90 protein in both the procyclic and the bloodstream forms (Fig.…”

Section: Resultsmentioning

confidence: 64%

Protein phosphatase 5 is required for Hsp90 function during proteotoxic stresses in Trypanosoma brucei

et al. 2008

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Trypanosoma brucei, a parasitic protozoan that causes African trypanosomiasis in human and domestic animals, adapt in various environments during their digenetic life cycle. In this study, we found that Hsp90 is crucial for the survival of this parasite. Inhibition of Hsp90 activity by geldanamycin (GA) reduced cell growth and increased the level of Hsp90. Both the bloodstream and procyclic forms of T. brucei showed a several-fold greater sensitivity than the mammalian cells to GA and also to 17-AAG, a less toxic derivative of GA, suggesting that Hsp90 could be a potential chemotherapeuric target for African trypanosomiasis. T. brucei Hsp90 interacts with the protein phosphatase 5 (PP5) in vivo. Under normal growth conditions, T. brucei PP5 (TbPP5) and Hsp90 are primarily localized in the cytosol. However, with increase in growth temperature and GA treatment, these proteins translocate to the nucleus. Overproduction of TbPP5 by genetic manipulation reduced the growth inhibitory effect of GA, while knockdown of TbPP5 reduced cell growth more in the presence of GA, as compared to parental control. Depletion of TbPP5, however, did not prevent the induction of Hsp90 protein level during GA treatment. Together, these results suggest that TbPP5 positively regulates the function of Hsp90 to maintain cellular homeostasis during proteotoxic stresses in T. brucei.

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Inhibition of HSP90 in Trypanosoma cruzi Induces a Stress Response but No Stage Differentiation

Cited by 75 publications

References 33 publications

Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases

Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases

Characterizing heat shock protein 90 gene of Apolygus lucorum (Meyer-Dür) and its expression in response to different temperature and pesticide stresses

Protein phosphatase 5 is required for Hsp90 function during proteotoxic stresses in Trypanosoma brucei

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