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Antimalarial activity of the anticancer histone deacetylase inhibitor SB939.

ABSTRACT: Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC(50)], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC(50), ~150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.

SUBMITTER: Sumanadasa SD

PROVIDER: S-EPMC3393387 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Antimalarial activity of the anticancer histone deacetylase inhibitor SB939.

Sumanadasa Subathdrage D M SD Goodman Christopher D CD Lucke Andrew J AJ Skinner-Adams Tina T Sahama Ishani I Haque Ashraful A Do Tram Anh TA McFadden Geoffrey I GI Fairlie David P DP Andrews Katherine T KT

Antimicrobial agents and chemotherapy 20120416 7

Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybackin ...[more]

PMID: 22508312

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Project description:HC-toxin, a cyclic peptide made by the filamentous fungus Cochliobolus carbonum, is an inhibitor of histone deacetylase (HDAC) from many organisms. It was shown earlier that the HDAC activity in crude extracts of C. carbonum is relatively insensitive to HC-toxin as well as to the chemically unrelated HDAC inhibitors trichostatin and D85, whereas the HDAC activity of Aspergillus nidulans is sensitive (G. Brosch et al., Biochemistry 40:12855-12863, 2001). Here we report that HC-toxin-resistant HDAC activity was present in other, but not all, plant-pathogenic Cochliobolus species but not in any of the saprophytic species tested. The HDAC activities of the fungi Alternaria brassicicola and Diheterospora chlamydosporia, which also make HDAC inhibitors, were resistant. The HDAC activities of all C. carbonum isolates tested, except one non-toxin-producing isolate, were resistant. In a cross between a sensitive isolate and a resistant isolate, resistance genetically cosegregated with HC-toxin production. When fractionated by anion-exchange chromatography, extracts of resistant and sensitive isolates and species had two peaks of HDAC activity, one that was fully HC-toxin resistant and a second that was larger and sensitive. The first peak was consistently smaller in extracts of sensitive fungi than in resistant fungi, but the difference appeared to be insufficiently large to explain the differential sensitivities of the crude extracts. Differences in mRNA expression levels of the four known HDAC genes of C. carbonum did not account for the observed differences in HDAC activity profiles. When mixed together, resistant extracts protected extracts of sensitive C. carbonum but did not protect other sensitive Cochlibolus species or Neurospora crassa. Production of this extrinsic protection factor was dependent on TOXE, the transcription factor that regulates the HC-toxin biosynthetic genes. The results suggest that C. carbonum has multiple mechanisms of self-protection against HC-toxin.

Dataset Information

Antimalarial activity of the anticancer histone deacetylase inhibitor SB939.

Publications

Antimalarial activity of the anticancer histone deacetylase inhibitor SB939.

Similar Datasets

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