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Psammaplin a Is a Natural Prodrug That Inhibits Class I Histone Deacetylase

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Psammaplin a Is a Natural Prodrug That Inhibits Class I Histone Deacetylase EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 39, No. 1, 47-55, February 2007 Psammaplin A is a natural prodrug that inhibits class I histone deacetylase 1 2 Dong Hoon Kim , Jongheon Shin Introduction 1,3 and Ho Jeong Kwon Reversible acetylation of core histones is controlled 1 by two families of enzymes, histone acetylases Department of Biotechnology (HATs) and histone deacetylases (HDACs), respec- College of Engineering, Yonsei University tively (Davie, 1998). Notably, perturbation of the Seoul 120-749, Korea 2 balance between HAT and HDAC activities in normal Natural Products Research Institute cells and aberrant recruitment of HDACs by onco- College of Pharmacy, Seoul National University genic proteins are implicated in several malignant Seoul 110-460, Korea 3 diseases including cancer (Marks et al., 1978; Corresponding author: Tel, 82-2-2123-5883; Fax, 82-2-362-7265; Dhordain et al., 1998; Kim et al., 2001; 2005; E-mail, [email protected] Pandolfi, 2001). HDAC is a hydrolase that has a zinc-binding site Accepted 6 December 2006 in tubular catalytic domain. All eleven human HDACs have deacetylase activity that is inhibited by small Abbreviations: BAECs, bovine aortic endothelial cells; BSO, butio- molecule such as a trichostatin A (TSA). Hyper- nine sulfoximine; HAT, histone acetylatransferase; HDAC, histone acetylation of histones resulted from the inhibition of deacetylase; Psam A, psammaplin A; Psams, psammaplins; SAHA, HDAC by specific inhibitors is physiologically linked suberoylanilide hydroxamic acid; TSA, trichostatin A to several cellular phenotypes such as cell-cycle arrest, cell-differenciation and cell death (Hoshikawa et al., 1994; Van Lint et al., 1996; Saito et al., 1999; Abstract Kim et al., 2003). Recently, inhibition of HDAC has been proposed for the treatment of cancer as well as Histone deacetylase (HDAC) has been highlighted as neurodegenerative disorders associated with muta- one of key players in tumorigenesis and angio - tions in polyglutamine-encoding tract (Hockly et al., genesis. Recently, several derivatives of psam - 2003). Accordingly, the inhibition of HDAC is a maplin (Psams) from a marine sponge have been rapidly growing and very promising area for the known to inhibit the HDAC activity, but the molecular development of anticancer drug (Vanhaecke et al., mechanism for the inhibition has not fully un - 2004). To date, several small molecules from natural derstood. Here, we explored the mode of action of sources and from chemical libraries have been de- Psams for the inhibition of HDAC activity in the veloped as HDAC inhibitors with an aim for develop- molecular and cellular level. Among the derivatives, ing new anticancer agents (Piekarz et al., 2001; psammaplin A (Psam A) showed the potent inhibitory Kelly et al., 2003). Interestingly, FK228, one of na- activity in enzyme assay and anti-proliferation assay tural HDAC inhibitors, exhibited a unique mode of with IC50 value of 0.003 and 1 µM, respectively. Psam action leading to the compound to be the first A selectively induced hyperacetylation of histones in prodrug targeting HDAC (Furumai et al., 2002). The the cells, resulting in the upregulation of gelsolin, a reducing agent such as glutathione mediated re- well-known HDAC target gene, in a transcriptional duction of a disulfide bond in the FK228 converts the level. In addition, reduced Psam A showed a stronger compound to be active leading to the coordination of inhibitory activity than that of non-reduced one. sulfhydryl group to the zinc metal ion located at the Notably, glutathione-depleted cells were not sensi- HDAC catalytic pocket. Indeed, sulfhydryl group of FK228 and glutathione conjugates in blood were tive to Psam A, implying that cellular reduction of the detected recently (Xiao et al., 2003). Consequently, compound is responsible for the HDAC inhibition of small molecules having a similar activity with FK228 Psam A after uptake into the cells. Together, these are valuable to be developed as they can decrease data demonstrate that Psam A could exhibit its non-specific binding of the compound to cellular activity under the reduced condition in the cells and proteins that may contribute some side-effects or be a new natural prodrug targeting HDAC. cytotoxicity of the compound. Thereafter, several HDAC inhibitors have been developed as HDAC Keywords: antineoplastic agents; histone deacety- prodrugs due to their clinical benefits (Batova et al., lases; prodrugs; psammaplin A 2002; Nishino et al., 2003; Yurek-George et al., 48 Exp. Mol. Med. Vol. 39(1), 47-55, 2007 o 2004). tained at 37 C under a humidified atmosphere of 5% Psammaplin A (Psam A) isolated from a marine CO2 in DMEM (Gibco, Grand Island, NY) supple- sponge was originally reported as an inhibitor of mented with 10% (v/v) heat-inactivated fetal bovine mycothiol-S-conjugate amidase and topoisomerase serum (FBS, Gibco), and 1% antibiotics (Gibco) (Hur II (Kim et al., 1999; Nicholas et al., 2003) and the et al., 2005). The cells were plated on 96 well-plates, compound, more recently, showed anticancer acti- and incubated under a condition described above. vity against several cancer cell lines and A549 lung After 24 h, the cells were treated with various xenograph mouse model (Park et al., 2003; Pina et compounds for 3 days. Then, proliferation of the al., 2003). However, little is known about its mode of cells was measured using MTT assay, and mor- action to suppress carcinogenic properties of the phology of the cells was observed using optical mi- cells. In our previous study, we found that Psam A croscopy at a × 100 magnification (Olympus Optical suppresses angiogenesis in vitro through the inhi- Inc., Melville, NY). bition of aminopeptidase N (APN), a zinc dependent metalloproteinase that plays a crucial role in meta- In vitro enzyme assay static tumor cell invasion (Shim et al., 2004). This finding opened a possibility, in part, to explain the HDAC enzymatic assay was performed with HDAC antitumor activity of Psam A, although it required Fluorescent Activity Assay kit (Biomol, Plymouth micromolar range of concentration to inhibit APN in Meeting, PA) according to the manufacturer’s in- vitro. Another plausible mechanism of Psam A for its struction. Briefly, nuclear fraction obtained from the anti-cancer activity was proposed by Crews group cultured cells was lysed with 0.5% Triton X-100 in (Pina et al., 2003). They showed that psammaplins phosphate buffer (pH 8.0) and used as an enzyme inhibited both activities of HDAC and DNA methyl- source of HDAC. Using 10 µg of protein, each transferase (DNMT) at the nanomolar concentraton reaction was performed as manufacturer’s instruc- in vitro, yet there was no detailed study on their tion in a 96 well-plate. After the reaction, HDAC HDAC inhibitory activity and mechanism in the cells. activity was measured with a GENios microplate In this study, we investigated the inhibitory activity fluorometer having the Magellan software system of several Psam derivatives against HDAC in the (TECAN, Austria) with excitation at 360 nm and cells and found that Psams, especially Psam A, can emission at 465 nm (Kim et al., 2005). be reduced by a reducing agent and reduction of the compound is responsible for the release of a Western blot analysis of acetylated proteins zinc-binding thiol group for its biological activity. This HeLa cells were cultured in 100 mm dish under a result provides a new insight how Psam A inhibits condition described above, and were treated with the the HDAC activity in the cells, and demonstrates that compounds for 8 h. After incubation, the cells were Psam A could be a new natural prodrug targeting washed and harvested by centrifugation. The cells HDAC. were then subjected to lysis with 0.5% Triton X-100 in PBS and samples were electrophoresed in 12.5% Materials and Methods SDS-PAGE and immunoblotted onto a PVDF mem- brane. Membrane was incubated with antibodies Chemicals against acetylated histone or tubulin (Upstate Bio- technology), and subsequently with -rabbit or Psam A and its analogues were isolated from a mouse antibodies (Amersham Pharmacia Biotech marine sponge as described previously (Jung et al., Inc., Piscataway, NJ). Acetylated proteins were de- 1995). Suberoylanilide hydroxamic acid (SAHA) was tected using chemiluminescence kit (Pierce, Rock- synthesized in our laboratory as described pre- ford, IL). The induction fold of proteins was viously (Richon et al., 1996), and FK228 was kindly quantified by LAS densitometry (Fujifilm, Japan). provided by Dr. Nakajima at Astellas Co., Japan. All stock concentrations were made in methanol and o stored at -20 C. Butionine sulfoximine (BSO) and Reverse transcriptase-Polymerase dithiothreitol (DTT) were purchased from Sigma chrain reaction (RT-PCR) (Sigma, St. Louis, MO). Protein A agarose beads HeLa cells were treated with Psam A and SAHA for was obtained from Upstate (Upstate biotechnology, 12 h, and total RNA was prepared. The synthesis of Lake Placid, NY). cDNA and a standard PCR were performed as described previously (Kim et al., 2002). Primer pairs Cell culture and proliferation assay used for RT-PCR are as the following: 5'-AGA- TCTGGCGTGTGGAGAAGTTCGA-3' and 5'-CTTT- Human cervical carcinoma cells (HeLa) were main- GACCTGGAAGAGTCTCTGCAC-3' for gelsolin, and Psmmaphilin A is a natural prodrug targeting HDAC 49 5'-CCTGACCCTGAAGTACCCCA-3' and 5'-CGTC- Data analysis and statistics ATGCAGCTCATAGCTC-3' for actin. PCR ampli- Data were presented as means ± SD or as the fication conditions of each gene are as followings; o percentage of control. Statistical comparisons bet- 57 C of annealing T and 27 cycles for actin, and t o ween groups were performed using the Student’s 60 C of annealing T and 30 cycles for gelsolin. The test. *P ＜ 0.05 was considered statistically signi- PCR products were resolved by 1% agarose gel ficant. electrophoresis. The induction fold of mRNA was quantified by LAS densitometry (Fujifilm, Japan).
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