Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

Abstract

Oxam¯atin [(2E) -5 -[3 -[(phenylsufonyl) amino] phenyl]-pent-2-en-4-ynohydroxamic acid] induces transcriptional activation of junD and morphological reversion in various NIH3T3-derived transformed cell lines. We found that oxam¯atin showed in vitro antiproliferative activity against various mouse and human tumor cell lines with drastic changes in the cell morphology and in vivo antitumor activity against B16 melanoma. Oxam¯atin caused an elongated cell shape with ®lamentous protrusions as well as arrest of the cell cycle at the G1 phase in HeLa cells. These phenotypic changes of HeLa cells were apparently similar to those by trichostatin A (TSA), a speci®c inhibitor of histone deacetylase (HDAC). The e ect of oxam¯atin on the transcriptional activity of the cytomegalovirus (CMV) promoter was examined and compared with known HDAC inhibitors, TSA, sodium n-butyrate, and FR901228. Oxam¯atin as well as all these inhibitors greatly enhanced the transcriptional activity of the CMV promoter in a dose-dependent manner. Oxam¯atin, like TSA, inhibited intracellular HDAC activity, as a result of which marked amounts of acetylated histone species accumulated. Finally, e ects on expression of several endogenous genes involved in cell morphology and cell cycle control in HeLa cells were analysed. Expression of gelsolin, cyclin E and Cdk inhibitors including p21 WAF1/Cip1 was highly augmented, while that of cyclin A and cyclin D1 was decreased by oxam¯atin. These results suggest that changes in the expression pattern of the genes regulating cell morphology and the cell cycle due to histone hyperacetylation are responsible for the antitumor activity, the morphological change and the cell cycle arrest induced by oxam¯atin.

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

“…HDAC4 silencing induces expression of p21 WAF1/Cip1 mRNA and protein HDAC inhibitors induce p21 WAF1/Cip1 in many cancer cell lines Sowa et al, 1997;Archer et al, 1998;Kim et al, 1999;Sambucetti et al, 1999;Han et al, 2000;Huang and Pardee, 2000;Richon et al, 2000;Sawa et al, 2004;Rocchi et al, 2005) and inhibit class I and class II HDACs equally well. To identify the specific HDACs that participate in regulating p21 WAF1/Cip1 , we transfected IGROV-1 cells with siRNAs directed against seven class I and II HDACs (HDAC1 through HDAC7) (Supplementary Figure S1A and B) and examined p21 WAF1/Cip1 by real-time polymerase chain reaction (RT-PCR) and western blot analysis.…”

“…As HDAC inhibitors regulate p21 WAF1/Cip1 gene transcription by modifying histone acetylation in the Kim et al, 1999;Sambucetti et al, 1999;Richon et al, 2000;Sawa et al, 2004), we used chromatin immunoprecipitation assays to analyse histone H3 acetylation at the Sp1/ Sp3-binding sites-rich region of the p21 WAF1/Cip1 promoter in HDAC4-silenced HeLa cells. Efficient HDAC4-silencing (Figure 4d, left) significantly increased histone H3 acetylation at the p21 WAF1/Cip1 promoter but not at the actin promoter used as a negative control (Figure 4d, right).…”

“…Among the genes that are consistently upregulated in cancer cells treated with HDAC inhibitors is the cell cycle mediator p21 WAF1/Cip1 Sowa et al, 1997;Archer et al, 1998;Kim et al, 1999;Saito et al, 1999;Sambucetti et al, 1999;Richon et al, 2000;Han et al, 2001;Rocchi et al, 2005). p21 WAF1/Cip1 arrests cell growth by inhibiting cyclin/Cdk complexes (Xiong et al, 1993) and can act as tumor suppressor gene by negatively regulating the cell cycle.…”

Histone Deacetylase Inhibitors for Cancer Therapy

“…[27][28][29][37][38][39] TSA, SAHA, oxamflatin, pyroxamide, and scriptaid, members of this class of inhibitors, potently and reversibly inhibit class I and II HDACs at nanomolar to micromolar concentrations in vitro. [49][50][51][52][53][54] Among them, TSA, initially isolated as an anti-fungal antibiotic from Streptomyces hygroscopicus, is widely used as a reference HDACI in research. However, its toxicity and low bioavailability have motivated the search for other molecules.…”

Novel Sulfonamide Derivatives as Inhibitors of Histone Deacetylase

“…Similar effects on cell cycle and differentiation have been observed with a number of deacetylase inhibitors [19]. Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g., liver fibrosis and liver cirrhosis [20].…”