Anticancer properties of distinct antimalarial drug classes

• 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; Parasites; Peroxides; Peroxides - pharmacology; Pharmaceutical sciences; Plasmodium; Pyrimethamine; Selectivity; Studies; Tetrahydrofolate dehydrogenase; Vector-borne diseases; Vincristine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0082962

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.