Ex VivoActivity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates ofPlasmodium falciparumandP. vivax

Abstract

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 [IC 50 s] of 310, 533, and 266 nM) and P. vivax (median IC 50 s 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.

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

“…The HAT inhibitor anacardic acid is also effective against parasites in culture, although with an IC 50 of >30 µM (23). Inhibition of parasite HDACs has provided more potent compounds against parasite growth and proliferation (26)(27)(28)46). For example, parasite killing by apicidin is reported with an IC 90 of 90 nM, and the hydroxamate trichostatin A has been shown to inhibit parasite growth with an IC 50 of ∼10 nM (47).…”

Potent Ex Vivo Activity of Naphthoquine and Methylene Blue against Drug-Resistant Clinical Isolates of Plasmodium falciparum and Plasmodium vivax

“…Drug plates were predosed with the standard antimalarials CQ, AQ, PIP, mefloquine (MFQ), and artesunate The drug susceptibility of P. vivax and P. falciparum isolates was measured using a protocol modified from the WHO microtest as described previously (33,35,36). In brief, 200 l of a 2% hematocrit blood media mixture (BMM), consisting of RPMI 1640 medium plus 10% AB ϩ human serum (P. falciparum) or McCoy's 5A medium plus 20% AB ϩ human serum (P. vivax) was added to each well of predosed drug plates containing 11 serial concentrations (2-fold dilutions) of the antimalarials (maximum concentration shown in parentheses) CQ (2,993 nM), AQ (158 nM), PIP (1,029 nM), MFQ (338 nM), AS (49 nM), NQ (481 nM), and MB (51 nM).…”

Comparative Ex Vivo Activity of Novel Endoperoxides in Multidrug-Resistant Plasmodium falciparum and P. vivax

“…Plasmodium drug susceptibility was measured using a protocol modified from the WHO microtest as described previously (17,31 Thick blood films made from each well were stained with 5% Giemsa solution for 30 min and examined microscopically. The number of schizonts per 200 asexual stage parasites was determined for each drug concentration and normalized to that of the control well.…”