Anticancer properties of distinct antimalarial drug classes

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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere82962
JournalPLoS One
Volume8
Issue number12
DOIs
StatePublished - Dec 31 2013

Fingerprint

Folic Acid Antagonists
antimalarials
Antimalarials
dihydrofolate reductase
dihydroartemisinin
Peroxides
artemisinin
neoplasms
Artemisinins
peroxides
Pyrimethamine
mechanism of action
Neoplasms
Cluster analysis
Vincristine
pyrimethamine
Microarrays
vincristine
Gene expression
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Van Huijsduijnen, R. H., Guy, R. K., Chibale, K., Haynes, R. K., Peitz, I., Kelter, G., ... Wells, T. N. C. (2013). Anticancer properties of distinct antimalarial drug classes. PLoS One, 8(12), [e82962]. https://doi.org/10.1371/journal.pone.0082962

Anticancer properties of distinct antimalarial drug classes. / Van Huijsduijnen, Rob Hooft; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N C.

In: PLoS One, Vol. 8, No. 12, e82962, 31.12.2013.

Research output: Contribution to journalArticle

Van Huijsduijnen, RH, Guy, RK, Chibale, K, Haynes, RK, Peitz, I, Kelter, G, Phillips, MA, Vennerstrom, JL, Yuthavong, Y & Wells, TNC 2013, 'Anticancer properties of distinct antimalarial drug classes', PLoS One, vol. 8, no. 12, e82962. https://doi.org/10.1371/journal.pone.0082962
Van Huijsduijnen RH, Guy RK, Chibale K, Haynes RK, Peitz I, Kelter G et al. Anticancer properties of distinct antimalarial drug classes. PLoS One. 2013 Dec 31;8(12). e82962. https://doi.org/10.1371/journal.pone.0082962
Van Huijsduijnen, Rob Hooft ; 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. In: PLoS One. 2013 ; Vol. 8, No. 12.
@article{98021c29f6ba4e2f953b3724fe6a9593,
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.",
author = "{Van Huijsduijnen}, {Rob Hooft} and Guy, {R. Kiplin} and Kelly Chibale and Haynes, {Richard K.} and Ingmar Peitz and Gerhard Kelter and Phillips, {Margaret A.} and Vennerstrom, {Jonathan L.} and Yongyuth Yuthavong and Wells, {Timothy N C}",
year = "2013",
month = "12",
day = "31",
doi = "10.1371/journal.pone.0082962",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Anticancer properties of distinct antimalarial drug classes

AU - Van Huijsduijnen, Rob Hooft

AU - Guy, R. Kiplin

AU - Chibale, Kelly

AU - Haynes, Richard K.

AU - Peitz, Ingmar

AU - Kelter, Gerhard

AU - Phillips, Margaret A.

AU - Vennerstrom, Jonathan L.

AU - Yuthavong, Yongyuth

AU - Wells, Timothy N C

PY - 2013/12/31

Y1 - 2013/12/31

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84894252057&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894252057&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0082962

DO - 10.1371/journal.pone.0082962

M3 - Article

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - e82962

ER -