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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Anticancer properties of distinct antimalarial drug classes
PLoS ONE, Volume 8, No. 12, Article e82962, Year 2013
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Description
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 IC50s 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 IC50s 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. © 2013 Hooft van Huijsduijnen et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3877007/bin/pone.0082962.s001.xlsx
Authors & Co-Authors
Hooft Van Huijsduijnen, Rob A.M.
Switzerland, Geneve
Medicines for Malaria Venture Mmv
Guy, R. Kiplin
United States, Memphis
St. Jude Children's Research Hospital
Chibale, Kelly
South Africa, Cape Town
University of Cape Town
Haynes, Richard K.
South Africa, Potchefstroom
North-west University
Peitz, Ingmar
United States, Wilmington
Charles River Laboratories, Inc.
Kelter, Gerhard
United States, Wilmington
Charles River Laboratories, Inc.
Phillips, Margaret A.
United States, Dallas
Ut Southwestern Medical School
Vennerstrom, Jonathan L.
United States, Omaha
The Nebraska Medical Center
Yuthavong, Yongyuth
Thailand, Pathum Thani
Thailand National Center for Genetic Engineering and Biotechnology
Wells, Timothy N.C.
Switzerland, Geneve
Medicines for Malaria Venture Mmv
Statistics
Citations: 71
Authors: 10
Affiliations: 8
Identifiers
Doi:
10.1371/journal.pone.0082962
e-ISSN:
19326203
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases