Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents.
The histones of Plasmodium falciparum represent a potential new target for anti-malarial compounds. A naturally occurring compound, apicidin, has recently been shown to inhibit the in vitro growth of P. falciparum. Apicidin was shown to hyperacetylate histones, suggesting that its mode of action is through histone deacetylase inhibition. We have tested the ability of known histone deacetylase inhibitors, mammalian tumour suppressor compounds, and cytodifferentiating agents to inhibit the in vitro growth of a drug sensitive and resistant strain of P. falciparum. Seven of the tested compounds had microM IC50 values, and trichostatin A, a histone deacetylation inhibitor and cytodifferentiating agent, was active at low nM concentrations. One compound, suberic acid bisdimethylamide, which selectively arrests tumour cells as opposed to normal mammalian cells, had an in vivo cytostatic effect against the acute murine malaria Plasmodium berghei, and one round of treatment with the compound failed to select for resistant mutations. These results suggest a promising role for histone deacetylase inhibitors and cytodifferentiating agents as antimalarial drug candidates.
Andrews
K T
KT
The Queensland Institute of Medical Research, PO Royal Brisbane Hospital, 300 Herston Road, Queensland 4029, Brisbane, Australia. Kathy_Andrews@med.uni-heidelberg.de
Walduck
A
A
Kelso
M J
MJ
Fairlie
D P
DP
Saul
A
A
Parsons
P G
PG
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006397:Hematinics / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects*
D000081:Acetamides; D000962:Antimalarials; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006397:Hematinics; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C107648:azelaic bishydroxamic acid; C014026:hexamethylene bisacetamide; D001374:Azacitidine