Anticancer properties of distinct antimalarial drug classes

Hooft  van Huijsduijnen, Rob; Guy, R Kiplin; Chibale, Kelly; Haynes, Richard K; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A; Vennerstrom, Jonathan L; Yuthavong, Yongyuth; Wells, Timothy N C

Anticancer properties of distinct antimalarial drug classes

Journal Article

2013

Journal Title

PLoS One

Link to Journal

http://journals.plos.org/plosone

Publisher

Public Library of Science

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

License

http://creativecommons.org/licenses/by/4.0

Abstract

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.