Inhibition of toxoplasma gondii and plasmodium falciparum infections in vitro by nsc3852, a redox active anti proliferative and tumor cell differentiation agent

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dc.contributor.authorStrobl, J. S.en
dc.contributor.authorSeibert, C. W.en
dc.contributor.authorLi, Y. B.en
dc.contributor.authorNagarkatti, R.en
dc.contributor.authorMitchell, S. M.en
dc.contributor.authorRosypal, A. C.en
dc.contributor.authorRathore, D.en
dc.contributor.authorLindsay, David S.en
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessed2014-06-16en
dc.date.accessioned2014-06-20T14:13:15Zen
dc.date.available2014-06-20T14:13:15Zen
dc.date.issued2009-02en
dc.description.abstractWe searched the National Cancer Institute (NCI) compound library for structures related to the antitumor quinoline NSC3852 (5-nitroso-8-quinolinol) and used a computer algorithm to predict the antiprotozoan activity for each of 13 structures. Half of these compounds inhibited Toroplastna gondii tachyzoite propagation in human fibroblasts at <= 1 mu M. The active compounds comprise a series of low-molecular-weight quinolines bearing nitrogen substituents in the ring-5 position. NSC3852 (EC(50) 80 nM) and NSC74949 (EC(50) 646 nM) were the most potent. NSC3852 also inhibited Plasmodium falciparum growth in human red blood cells (EC(50) 1.3 mu M). To investigate the mechanism for NSC3852's anti-T. gondii activity, we used chemiluminescence assays to detect reactive oxygen species (ROS) formation in freshly isolated tachyzoites and in infected host cells; the absence of ROS generation by NSC3852 in these assays indicated NSC3852 does not redox cycle in T. gondii. Inhibitors of enzyme sources of free radicals such as superoxide anion, nitric oxide (NO), and their reaction product peroxynitrite did not interfere with the anti-T. gondii activity of NSC3852. However, inhibition of T. gondii tachyzoite propagation by NSC3852 involved redox reactions because tachyzoites were protected from NSC3852 by inclusion of the cell permeant superoxide dismutase mimetic, MnTMPyP or N-acetylcysteine in the culture medium. We conclude that the Prediction of Activity Spectra for Substances (PASS) computer program is useful in finding new compounds that inhibit T. gondii tachyzoites in vitro and that NSC3852 is a potent T. gondii inhibitor that: acts by indirect generation of oxidative stress in T. gondii.en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationJeannine S. Strobl, Christopher W. Seibert, Yunbo Li, Rana Nagarkatti, Sheila M. Mitchell, Alexa C. Rosypal, Dharmendar Rathore, and David S. Lindsay (2009). "Inhibition of Toxoplasma gondii and Plasmodium falciparum Infections in Vitro by NSC3852, a Redox Active Antiproliferative and Tumor Cell Differentiation Agent," Journal of Parasitology, Vol. 95, No. 1, pp. 215-223. doi: http://dx.doi.org/10.1645/GE-1608.1en
dc.identifier.doihttps://doi.org/10.1645/ge-1608.1en
dc.identifier.issn0022-3395en
dc.identifier.urihttp://hdl.handle.net/10919/49053en
dc.identifier.urlhttp://www.bioone.org/doi/abs/10.1645/GE-1608.1en
dc.language.isoenen
dc.publisherAmerican Society of Parasitologyen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectparasitic infectionsen
dc.subjectunited-statesen
dc.subjectnitric-oxideen
dc.subjectt-cellsen
dc.subjectschizophreniaen
dc.subjectApoptosisen
dc.subjectmanifestationsen
dc.subjecttransmissionen
dc.subjectmacrophagesen
dc.subjectfibroblastsen
dc.subjectparasitologyen
dc.titleInhibition of toxoplasma gondii and plasmodium falciparum infections in vitro by nsc3852, a redox active anti proliferative and tumor cell differentiation agenten
dc.title.serialJournal of Parasitologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
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