Anticancer properties of distinct antimalarial drug classes

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dc.contributor.authorHooft van Huijsduijnen, Roben_ZA
dc.contributor.authorGuy, R Kiplinen_ZA
dc.contributor.authorChibale, Kellyen_ZA
dc.contributor.authorHaynes, Richard Ken_ZA
dc.contributor.authorPeitz, Ingmaren_ZA
dc.contributor.authorKelter, Gerharden_ZA
dc.contributor.authorPhillips, Margaret Aen_ZA
dc.contributor.authorVennerstrom, Jonathan Len_ZA
dc.contributor.authorYuthavong, Yongyuthen_ZA
dc.contributor.authorWells, Timothy N Cen_ZA
dc.date.accessioned2015-11-18T07:16:06Z
dc.date.available2015-11-18T07:16:06Z
dc.date.issued2013en_ZA
dc.description.abstractWe have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC 50 s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC 50 s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.en_ZA
dc.identifier.apacitationHooft van Huijsduijnen, R., Guy, R. K., Chibale, K., Haynes, R. K., Peitz, I., Kelter, G., ... Wells, T. N. C. (2013). Anticancer properties of distinct antimalarial drug classes. <i>PLoS One</i>, http://hdl.handle.net/11427/15157en_ZA
dc.identifier.chicagocitationHooft van Huijsduijnen, Rob, R Kiplin Guy, Kelly Chibale, Richard K Haynes, Ingmar Peitz, Gerhard Kelter, Margaret A Phillips, Jonathan L Vennerstrom, Yongyuth Yuthavong, and Timothy N C Wells "Anticancer properties of distinct antimalarial drug classes." <i>PLoS One</i> (2013) http://hdl.handle.net/11427/15157en_ZA
dc.identifier.citationHooft van Huijsduijnen, R., Guy, R. K., Chibale, K., Haynes, R. K., Peitz, I., Kelter, G., ... & Wells, T. N. (2012). Anticancer properties of distinct antimalarial drug classes. PloS one, 8(12), e82962. doi:10.1371/journal.pone.0082962en_ZA
dc.identifier.ris TY - Journal Article AU - Hooft van Huijsduijnen, Rob AU - Guy, R Kiplin AU - Chibale, Kelly AU - Haynes, Richard K AU - Peitz, Ingmar AU - Kelter, Gerhard AU - Phillips, Margaret A AU - Vennerstrom, Jonathan L AU - Yuthavong, Yongyuth AU - Wells, Timothy N C AB - We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC 50 s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC 50 s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. DA - 2013 DB - OpenUCT DO - 10.1371/journal.pone.0082962 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Anticancer properties of distinct antimalarial drug classes TI - Anticancer properties of distinct antimalarial drug classes UR - http://hdl.handle.net/11427/15157 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15157
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0082962
dc.identifier.vancouvercitationHooft van Huijsduijnen R, Guy RK, Chibale K, Haynes RK, Peitz I, Kelter G, et al. Anticancer properties of distinct antimalarial drug classes. PLoS One. 2013; http://hdl.handle.net/11427/15157.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2013 Hooft van Huijsduijnen et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherAntimalarialsen_ZA
dc.subject.otherGene expressionen_ZA
dc.subject.otherPeroxidesen_ZA
dc.subject.otherApoptosisen_ZA
dc.subject.otherDrug-drug interactionsen_ZA
dc.subject.otherCancer treatmenten_ZA
dc.subject.otherMalariaen_ZA
dc.subject.otherPyrimethamineen_ZA
dc.titleAnticancer properties of distinct antimalarial drug classesen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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