Psammaplin A is a natural prodrug that inhibits class I histone deacetylase.
Histone deacetylase (HDAC) has been highlighted as one of key players in tumorigenesis and angiogenesis. Recently, several derivatives of psammaplin (Psams) from a marine sponge have been known to inhibit the HDAC activity, but the molecular mechanism for the inhibition has not fully understood. Here, we explored the mode of action of Psams for the inhibition of HDAC activity in the molecular and cellular level. Among the derivatives, psammaplin A (Psam A) showed the potent inhibitory activity in enzyme assay and anti-proliferation assay with IC50 value of 0.003 and 1 muM, respectively. Psam A selectively induced hyperacetylation of histones in the cells, resulting in the upregulation of gelsolin, a well-known HDAC target gene, in a transcriptional level. In addition, reduced Psam A showed a stronger inhibitory activity than that of non-reduced one. Notably, glutathione-depleted cells were not sensitive to Psam A, implying that cellular reduction of the compound is responsible for the HDAC inhibition of Psam A after uptake into the cells. Together, these data demonstrate that Psam A could exhibit its activity under the reduced condition in the cells and be a new natural prodrug targeting HDAC.
Kim
Dong Hoon
DH
Department of Biotechnology, College of Engineering, Yonsei University, Seoul 120-749, Korea.
Shin
Jongheon
J
Kwon
Ho Jeong
HJ
D000107:Acetylation; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000145:classification* / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D001688:Biological Products; D004220:Disulfides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011355:Prodrugs; C098378:psammaplin A; D014443:Tyrosine; D006655:Histone Deacetylases