Anticancer properties of distinct antimalarial drug classes

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 prolif...

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Bibliographic Details
Published in:PloS one 2013-12, Vol.8 (12), p.e82962
Main Authors: 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
Format: Article
Language:English
Subjects:
Analysis
Angiogenesis
Anticancer properties
Antimalarial agents
Antimalarials
Antimalarials - administration & dosage
Antimalarials - classification
Antimalarials - pharmacology
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacology
Antineoplastic drugs
Antitumor agents
Apoptosis
Artemisinin
Artemisinins - pharmacology
Artesunate
Biology
Cancer
Cancer prevention
Cancer therapies
Cell Line, Tumor
Cell Proliferation - drug effects
Cisplatin
Cluster Analysis
Clusters
Cytotoxicity
Data processing
Dihydroartemisinin
Dihydrofolate reductase
Dihydroorotate dehydrogenase
DNA microarrays
Drug dosages
Drug Screening Assays, Antitumor
Drug Synergism
Drugs
Enzyme inhibitors
Folic Acid Antagonists - pharmacology
Gene expression
Gene Expression - drug effects
Humans
Imatinib
Inhibition
Inhibitors
Malaria
Medicine
Mode of action
Peroxides
Peroxides - pharmacology
Pharmaceutical sciences
Plasmodium
Pyrimethamine
Selectivity
Studies
Tetrahydrofolate dehydrogenase
Vector-borne diseases
Vincristine
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0082962