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Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939 Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939 Subathdrage D. M. Sumanadasa a , b , Christopher D. Goodman c , Andrew J. Lucke d , Tina Skinner-Adams b , Ishani Sahama b , e , Ashraful Haque b , Tram Anh Do d , Geoffrey I. McFadden c , David P. Fairlie d and Katherine T. Andrews a , b a Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Queensland, Australia b Queensland Institute of Medical Research, Brisbane, Queensland, Australia c School of Botany, University of Melbourne, Melbourne, Victoria, Australia d Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia e School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antimicrobial Agents and Chemotherapy American Society For Microbiology

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

Antimicrobial Agents and Chemotherapy , Volume 56 (7): 3849 – Jul 1, 2012

Abstract

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939 Subathdrage D. M. Sumanadasa a , b , Christopher D. Goodman c , Andrew J. Lucke d , Tina Skinner-Adams b , Ishani Sahama b , e , Ashraful Haque b , Tram Anh Do d , Geoffrey I. McFadden c , David P. Fairlie d and Katherine T. Andrews a , b a Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Queensland, Australia b Queensland Institute of Medical Research, Brisbane, Queensland, Australia c School of Botany, University of Melbourne, Melbourne, Victoria, Australia d Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia e School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia 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.

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References (68)

Publisher
American Society For Microbiology
Copyright
Copyright © 2012 by the American society for Microbiology.
ISSN
0066-4804
eISSN
1098-6596
DOI
10.1128/AAC.00030-12
pmid
22508312
Publisher site
See Article on Publisher Site

Abstract

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939 Subathdrage D. M. Sumanadasa a , b , Christopher D. Goodman c , Andrew J. Lucke d , Tina Skinner-Adams b , Ishani Sahama b , e , Ashraful Haque b , Tram Anh Do d , Geoffrey I. McFadden c , David P. Fairlie d and Katherine T. Andrews a , b a Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Queensland, Australia b Queensland Institute of Medical Research, Brisbane, Queensland, Australia c School of Botany, University of Melbourne, Melbourne, Victoria, Australia d Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia e School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia 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.

Journal

Antimicrobial Agents and ChemotherapyAmerican Society For Microbiology

Published: Jul 1, 2012

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