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Examination of the cytotoxic and embryotoxic potential and underlying mechanisms of next-generation synthetic trioxolane and tetraoxane antimalarials

2012Journal article Open Access
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dc.contributor.authorCopple, I. M.
dc.contributor.authorMercer, A. E.
dc.contributor.authorFirman, J.
dc.contributor.authorDonegan, G.
dc.contributor.authorHerpers, B.
dc.contributor.authorWong, M. H.
dc.contributor.authorChadwick, J.
dc.contributor.authorBringela, A.
dc.contributor.authorCristiano, Maria Lurdes Santos
dc.contributor.authorVan De Water, B.
dc.contributor.authorWard, Stephen A.
dc.contributor.authorO'Neill, Paul M.
dc.contributor.authorPark, B. K.
dc.date.accessioned2014-06-06T14:23:08Z
dc.date.available2014-06-06T14:23:08Z
dc.date.issued2012
dc.date.updated2014-05-30T16:23:23Z
dc.description.abstractSemisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria.por
dc.identifier.citationCopple IM; Mercer A.E.; Firman j.; Donegan G.; Herpers B.; Wong MH; Chadwick J.; Bringela A.D.; Cristiano, M.L.; Van De Water, B; Ward, Stephen A.; O’Neill, Paul M.; Park BK. EXAMINATION OF THE CYTOTOXIC AND EMBRYOTOXIC POTENTIAL, AND UNDERLYING MECHANISMS, OF NEXT-GENERATION SYNTHETIC TRIOXOLANE AND TETRAOXANE ANTIMALARIALS, Molecular Medicine, 18, 1045-1055, 2012.por
dc.identifier.issn1076-1551
dc.identifier.otherAUT: MCR00716;
dc.identifier.urihttp://hdl.handle.net/10400.1/4220
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherFeinstein Institute for Medical Researchpor
dc.relationTHE SAFETY PHARMACOLOGY OF ARTEMISININS WHEN USED TO REVERSE PATHOPHYSIOLOGY OF MALARIA IN PREGNANCY
dc.relation.publisherversionhttp://www.molmed.orgpor
dc.titleExamination of the cytotoxic and embryotoxic potential and underlying mechanisms of next-generation synthetic trioxolane and tetraoxane antimalarialspor
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTHE SAFETY PHARMACOLOGY OF ARTEMISININS WHEN USED TO REVERSE PATHOPHYSIOLOGY OF MALARIA IN PREGNANCY
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/200805/EU
oaire.citation.endPage1055por
oaire.citation.startPage1045por
oaire.citation.titleMolecular Medicinepor
oaire.citation.volume18por
oaire.fundingStreamFP7
person.familyNameCristiano
person.givenNameMaria de Lurdes
person.identifier.ciencia-idE411-6006-5A01
person.identifier.orcid0000-0002-9447-2855
person.identifier.ridG-2345-2012
person.identifier.scopus-author-id9238724800
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspor
rcaap.typearticlepor
relation.isAuthorOfPublicationb16751a6-748e-44b0-9c59-058cbd5b2cc3
relation.isAuthorOfPublication.latestForDiscoveryb16751a6-748e-44b0-9c59-058cbd5b2cc3
relation.isProjectOfPublicationfd48be2a-f84d-4785-bd94-e82bf286754c
relation.isProjectOfPublication.latestForDiscoveryfd48be2a-f84d-4785-bd94-e82bf286754c

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