TY - JOUR
T1 - Ex vivo activity of histone deacetylase inhibitors against multidrug-resistant clinical isolates of Plasmodium falciparum and P. vivax
AU - Marfurt, Jutta
AU - Chalfein, Ferryanto
AU - Prayoga, Pak
AU - Wabiser, Frans
AU - Kenangalem, Enny
AU - Piera, Kim
AU - Fairlie, David
AU - Tjitra, Emiliana
AU - Anstey, Nicholas
AU - Andrews, Kathy
AU - Price, Ric
PY - 2011
Y1 - 2011
N2 - Histone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitro activity against drug-resistant and -sensitive laboratory strains of P. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum (n = 24) and P. vivax (n = 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum (median 50% inhibitory concentrations [IC50s] of 310, 533, and 266 nM) and P. vivax (median IC50s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P. vivax schizont maturation, comparable to that in P. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.
AB - Histone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitro activity against drug-resistant and -sensitive laboratory strains of P. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum (n = 24) and P. vivax (n = 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum (median 50% inhibitory concentrations [IC50s] of 310, 533, and 266 nM) and P. vivax (median IC50s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P. vivax schizont maturation, comparable to that in P. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.
KW - 2 aminosuberic acid 14
KW - 2 aminosuberic acid 9
KW - artesunate
KW - chloroquine
KW - histone deacetylase inhibitor
KW - mefloquine
KW - piperaquine
KW - unclassified drug
KW - vorinostat
KW - wr 308364
KW - antimalarial activity
KW - antimalarial drug resistance
KW - antimalarial drug susceptibility
KW - article
KW - controlled study
KW - drug potency
KW - drug specificity
KW - drug structure
KW - ex vivo study
KW - growth inhibition
KW - IC 50
KW - Indonesia
KW - microbial growth
KW - microbial sensitivity test
KW - minimum inhibitory concentration
KW - multidrug resistance
KW - nonhuman
KW - Papua New Guinea
KW - Plasmodium falciparum
KW - Plasmodium vivax
KW - priority journal
KW - schizont
KW - species difference
KW - Drug Resistance, Multiple, Bacterial
KW - Histone Deacetylase Inhibitors
KW - Hydroxamic Acids
KW - Microbial Sensitivity Tests
UR - http://www.scopus.com/inward/record.url?scp=79952341758&partnerID=8YFLogxK
U2 - 10.1128/AAC.01220-10
DO - 10.1128/AAC.01220-10
M3 - Article
C2 - PubMed:21135175
SN - 0066-4804
VL - 55
SP - 961
EP - 966
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 3
ER -