Psammaplin A is a natural prodrug that inhibits class I histone deacetylase

Dong Hoon Kim,Ho Jeong Kwon,Jongheon Shin

doi:10.1038/emm.2007.6

Abstract

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.

Highlights

Reversible acetylation of core histones is controlled by two families of enzymes, histone acetylases (HATs) and histone deacetylases (HDACs), respectively (Davie, 1998)
HDAC activity inhibited by DTT-pretreated psammaplin A (Psam A) was recovered by addition of H2O2. These results demonstrate that Psam A can be reduced by a reducing agent, and this reduction is very important for HDAC inhibitory activity of Psam A
Inhibition of HDAC is an emerging new strategy for developing anticancer drugs, and various compounds from natural sources and chemical synthesis have been developed as HDAC inhibitors with an aim of developing new anticancer agents (Hoshikawa et al, 1994; Saito et al, 1999; Piekarz et al, 2001)

Summary

Introduction

Reversible acetylation of core histones is controlled by two families of enzymes, histone acetylases (HATs) and histone deacetylases (HDACs), respectively (Davie, 1998). FK228, one of natural HDAC inhibitors, exhibited a unique mode of action leading to the compound to be the first prodrug targeting HDAC (Furumai et al, 2002). The reducing agent such as glutathione mediated reduction of a disulfide bond in the FK228 converts the compound to be active leading to the coordination of sulfhydryl group to the zinc metal ion located at the HDAC catalytic pocket. Small molecules having a similar activity with FK228 are valuable to be developed as they can decrease non-specific binding of the compound to cellular proteins that may contribute some side-effects or cytotoxicity of the compound.

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Conclusion