title: Anticancer properties of distinct antimalarial drug classes.
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 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.
authors.affiliation: Medicines for Malaria Venture (MMV), Geneva, Switzerland.
authors.forename: Rob
authors.initials: R
authors.lastname: Hooft van Huijsduijnen
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Haynes
authors.affiliation: Oncotest GmbH, Freiburg, Germany.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Peitz
authors.affiliation: Oncotest GmbH, Freiburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kelter
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.affiliation: Department of Pharmaceutical Sciences, Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
authors.affiliation: BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani, Thailand.
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
authors.affiliation: Medicines for Malaria Venture (MMV), Geneva, Switzerland.
authors.forename: Timothy N C
authors.initials: TN
authors.lastname: Wells
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage / Q000145:classification* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D010545:Peroxides / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D005493:Folic Acid Antagonists; D010545:Peroxides