Biomedical subjects

Da-Sheng Wang

Publications and source records attributed to Da-Sheng Wang.

4 recordsLinked to original sources

PubMed2006

Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer.

PURPOSE: To assess the antitumor effects of a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, (S)-HDAC-42, vis-à-vis suberoylanilide hydroxamic acid (SAHA) in in vitro and in vivo models of human prostate cancer. EXPERIMENTAL DESIGN: The in vitro effects of (S)-HDAC-42 and SAHA were evaluated in PC-3, DU-145, or LNCaP human prostate cancer cell lines. Cell viability, apoptosis, and indicators of HDAC inhibition were assessed. Effects on Akt and members of the Bcl-2 and inhibitor of apoptosis protein families were determined by immunoblotting. Immunocompromised mice bearing established s.c. PC-3 xenograft tumors were treated orally with (S)-HDAC-42 (50 mg/kg q.o.d. or 25 mg/kg q.d.) or SAHA (50 mg/kg q.d.) for 28 days. In vivo end points included tumor volumes and intratumoral changes in histone acetylation, phospho-Akt status, and protein levels of Bcl-xL and survivin. RESULTS: (S)-HDAC-42 was more potent than SAHA in suppressing the viability of all cell lines evaluated with submicromolar IC50 values. Relative to SAHA, (S)-HDAC-42 exhibited distinctly superior apoptogenic potency, and caused markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. The growth of PC-3 tumor xenografts was suppressed by 52% and 67% after treatment with (S)-HDAC-42 at 25 and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppressed growth by 31%. Intratumoral levels of phospho-Akt and Bcl-xL were markedly reduced in (S)-HDAC-42-treated mice, in contrast to mice treated with SAHA. CONCLUSIONS: (S)-HDAC-42 is a potent orally bioavailable inhibitor of HDAC, as well as targets regulating multiple aspects of cancer cell survival, which might have clinical value in prostate cancer chemotherapy and warrants further investigation in this regard.

Administration, Oral↗

PubMed2006

Development of small-molecule cyclin D1-ablative agents.

Previously, we demonstrated that the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone mediated the repression of cyclin D1 in MCF-7 breast cancer cells by facilitating proteasome-facilitated proteolysis. This PPARgamma-independent mechanism provided a molecular basis for using troglitazone as scaffold to develop a novel class of cyclin D1-ablative agents. The proof of principle of this premise is provided by Delta2TG, in which the introduction of a double bond adjacent to the thiazolidinedione ring abrogated the PPARgamma activity while retaining the activity in cyclin D1 repression. Structural optimization of Delta2TG led to STG28 [(S)-5-(4-{[6-(allyloxy)-2,5,7,8-tetramethylchroman-2-yl]methoxy}-3-methoxybenzylidene)thiazolidine-2,4-dione], which exhibited low micromolar potency in ablating cyclin D1 and inhibiting MCF-7 cell proliferation. It is noteworthy that STG28 mediated the proteasomal degradation of cyclin D1 with a high degree of specificity. Exposure to STG28 did not cause any appreciable change in the expression levels of a series of other cyclins and CDK-dependent kinases. In light of the pivotal role of cyclin D1 in promoting tumorigenesis and drug resistance, this novel cyclin D1-ablating agent may have therapeutic relevance in cancer therapy.

Antineoplastic Agents↗

PubMed2006

alpha-Tocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 function.

Although the antitumor effect of alpha-tocopheryl succinate (vitamin E succinate) has been well demonstrated, its underlying mechanism remains elusive. This study provides evidence that inhibition of Bcl-xL/Bcl-2 function represents a major pathway whereby alpha-tocopheryl succinate mediates apoptosis induction in prostate cancer cells. In vitro data indicate that alpha-tocopheryl succinate was able to disrupt the binding of Bak BH3 peptide to Bcl-xL and Bcl-2 with IC50 of 26 microm, in line with its potency in antiproliferation. Treatment of PC-3 cells with this agent led to reduced association of Bcl-2 and Bcl-xL with Bak, leading to caspase-dependent apoptosis. Moreover, overexpression of Bcl-xL protected LNCaP cells from the apoptosis induction. This mechanistic finding provided a basis to develop potent Bcl-xL/Bcl-2 inhibitors. Docking of alpha-tocopheryl succinate into the Bak peptide-binding site indicates that it adopted a unique hairpin-shaped conformation for protein interactions. We rationalized that the hemisuccinate and the two proximal isopranyl units of the side chain played a crucial role in ligand anchoring and protein-ligand complex stabilization, respectively. However, exposure of the distal isopranyl unit to a polar environment might diminish the binding affinity of alpha-tocopheryl succinate. This premise was corroborated by a structure-activity analysis of a series of derivatives with truncated side chains and/or altered carboxyl terminus. This computer model predicted that the removal of the distal isopranyl unit from the side chain would improve binding affinity, leading to two agents with significantly higher potency in inhibiting Bak peptide binding and in suppressing prostate cancer cell proliferation.

Apoptosis↗

PubMed2005

Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors.

Previously, we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn(2+)-chelating motifs, which led to N-hydroxy-4-(4-phenylbutyryl-amino)benzamide (HTPB), a hydroxamate-tethered phenylbutyrate derivative with sub-micromolar potency in inhibiting HDAC activity and cancer cell proliferation. In this study, we carried out structure-based optimization of HTPB by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes. Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization. This premise was corroborated by the greater potency of (S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide [(S)-11] (IC(50) in HDAC inhibition, 16 nM), of which the isopropyl moiety was favorable in interacting with this hydrophobic motif. (S)-11 at concentrations as low as 0.1 microM was effective in causing histone hyperacetylation and p21(WAF/CIP1) overexpression and suppressing proliferation in cancer cells.

Acetylation↗