Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents.

Itazaki, Hiroshi; Nagashima, K.; Sakai, Kenji; Yoshida, Hiroshi; Kawamura, Yoshimi; Yasuda, Yukio; Matsumoto, Koichí; Ishii, Kikuo; Uotani, Nobuo; Nakai, Hiroshi; Terui, Akihiro; Yoshimatsu, Shinya; Ikenishi, Yuji; Nakagawa, Yuzo

doi:10.7164/antibiotics.43.1524

Cited by 195 publications

(107 citation statements)

References 15 publications

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“…For instance, trichostatin A (TSA), trapoxin, and FR901228 revert the cell morphology of v-sis and v-ras-transformed cells to apparently normal ones (Futamura et al, 1995;Itazaki et al, 1990;Sugita et al, 1992;Ueda et al, 1994b). Histone deacetylases (HDAC) were shown to be the molecular targets of these agents (Kijima et al, 1993;Nakajima et al, 1998;Yoshida et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

et al. 1999

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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.

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Section: Introductionmentioning

confidence: 99%

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

et al. 1999

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“…Importantly, a number of small molecules based on natural products (trapoxin A (Itazaki et al, 1990;Kwon et al, 1998), trichostatin (Yoshida et al, 1995), apcidin (Kim et al, 2000) have all been tested and shown to have anti-tumoral potential in murine models. The literature is ever expanding and revealing new mechanisms by which chromatin remodeling is regulated in part by acetylation/deacetylation reactions.…”

Section: Histone Deacetylase Inhibitor Sahamentioning

confidence: 99%

New agents in cancer clinical trials

Adams

Elliott

2000

Oncogene

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“…2 Many investigators have also shown that histone deacetylase (HDAC) interacts with inactive and/or nonliganded transcription factors via corepressors such as mSin3A, N-CoR and SMRT to repress the transcription in mammalian cells. 3 On the basis of the molecular background, HDAC inhibitors (HDIs) such as butyrate, trichostatin A (TSA) 4,5 and trapoxin A (TPX) 6,7 were shown to release the repression, resulting in transcription of the target genes. Recently, three independent groups [8][9][10] demonstrated that HDI released the repression in vitro by a fusion protein, PML-RAR␣, which is responsible for acute promyelocytic leukemia (APL).…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy

et al. 1999

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We investigated the effect of the histone deacetylase inhibitors (HDIs), trichostatin A and trapoxin A on leukemia cells and cell lines from the viewpoint of differentiation induction. TSA induced differentiation in erythroid cell lines by itself, whereas it synergistically enhanced the differentiation that was directed by all-trans retinoic acid (ATRA) or vitamin D3 in U937, HL60 and NB4 cells. The combined treatment of HDI with ATRA induced differentiation in ATRA-resistant HL60 and NB4 cells. The transcriptional expression during the treatment with HDI was examined in HL60, U937 and MEG-O1. Cell cycle-regulator genes (p21 waf1 and p16 INK4A ) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, ␤-globin) were silent or downregulated, and housekeeping genes (␤-actin and GAPDH) were constantly expressed. Twelve of 35 (34%) clinical samples from AML patients ranging from M0 to M7 also displayed both phenotypical and morphological changes by the treatment with TSA alone. HDIs are thus the potent inducer or enhancer of differentiation in acute myeloid leukemia and regulate transcription in an ordered manner.

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Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents.

Abstract: for trapoxin B, by X-ray analysis, mass spectrometric, NMR and chemical studies.

Cited by 195 publications

References 15 publications

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

New agents in cancer clinical trials

Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy

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