Spiruchostatins A and B, novel gene expression-enhancing substances produced by Pseudomonas sp.

Masuoka, Yuhta; Nagai, Atsuko; Shin‐ya, Kazuo; Furihata, Kazuo; Nagai, Koji; Suzuki, Kenichi; Hayakawa, Yoichi; Seto, Haruo

doi:10.1016/s0040-4039(00)01874-8

Cited by 98 publications

(75 citation statements)

References 10 publications

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“…A clinical trial of entinostat and the anti-PD-L1 antibody atezolizumab for TNBC is also in progress (ClinicalTrial.gov Identifier: NCT02708680). OBP-801, originally known as spiruchostatin A, as an enhancer of plasminogen activator inhibitor-1 gene expression [8], was identified as a novel HDAC inhibitor in our previous study using p21 promoter-reporter screening [9]. OBP-801 showed the most potent HDAC inhibitory activity in our study, being about 50 times more effective than the HDAC inhibitor vorinostat [9].…”

Section: Introductionmentioning

confidence: 55%

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

Ono

Sowa

Horinaka

et al. 2018

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Eribulin was approved for the treatment of metastatic breast cancer through the EMBRACE trial, and a subgroup analysis in this clinical trial indicated the efficacy of eribulin in patients with TNBC. However, the prognosis of patients with TNBC is still poor due to various molecular characteristics. Therefore, there is an urgent need for a more effective treatment for the management of TNBC. Methods We investigated the synergistic effect of a novel histone deacetylase (HDAC) inhibitor, OBP-801, and eribulin in TNBC cell lines because OBP-801 has been known to enhance the anti-tumor activities of other chemotherapeutic agents. The cell growth was analyzed, and the flow cytometry analysis was conducted to evaluate the effects on cell cycle and the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC cell growth was investigated through Western blot analyses. Results The combination treatment of OBP-801 with eribulin showed the synergistic inhibition of the growth in TNBC cells, involved with the enhancement of apoptosis. We, for the first time, found that eribulin upregulated survivin and also that OBP-801 could remarkably suppress the upregulation of survivin by eribulin. Moreover, this combination potently suppressed Bcl-xL and the MAPK pathway compared with either agent alone. Conclusion We found that the combination of OBP-801 and eribulin synergistically inhibited the growth with apoptosis in TNBC cells, suggesting that this combination might be a promising novel strategy for treating TNBC patients.

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Section: Introductionmentioning

confidence: 55%

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

Ono

Sowa

Horinaka

et al. 2018

Breast Cancer Res Treat

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“…in a search for anticancer compounds that could mimic the antiproliferative effects of TGF-b 1 by the induction of genes that caused cell-cycle arrest (25). This search was based on the rationale that although the TGF-b 1 treatment of some cancer cells can result in an increased expression of p21 waf1 , a known cyclin-dependent kinase inhibitor (26,27), other cancers escape this growth inhibition by down-regulating TGF-b receptors.…”

Section: Discussionmentioning

confidence: 99%

“…This search was based on the rationale that although the TGF-b 1 treatment of some cancer cells can result in an increased expression of p21 waf1 , a known cyclin-dependent kinase inhibitor (26,27), other cancers escape this growth inhibition by down-regulating TGF-b receptors. Masuoka and colleagues (25) hypothesized that substances with the ability to induce the expression of growth-inhibitory genes independent of TGF-b 1 would be potential chemotherapeutic agents. Consistent with this hypothesis, SpA was shown to inhibit the proliferation of several types of cancer cells by an induction of cell-cycle regulators (15,18).…”

Section: Discussionmentioning

confidence: 99%

Spiruchostatin A Inhibits Proliferation and Differentiation of Fibroblasts from Patients with Pulmonary Fibrosis

Davies

Haitchi

Thatcher

et al. 2012

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disorder characterized by the proliferation of interstitial fibroblasts and the deposition of extracellular matrix causing impaired gas exchange. Spiruchostatin A (SpA) is a histone deacetylase inhibitor (HDI) with selectivity toward Class I enzymes, which distinguishes it from other nonspecific HDIs that are reported to inhibit (myo)fibroblast proliferation and differentiation. Because the selectivity of HDIs may be important clinically, we postulated that SpA inhibits the proliferation and differentiation of IPF fibroblasts. Primary fibroblasts were grown from lung biopsy explants obtained from patients with IPF or from normal control subjects, using two-dimensional or threedimensional culture models. The effect of SpA on fibroproliferation in serum-containing medium 6 transforming growth factor (TGF)-b 1 was quantified by methylene blue binding. The acetylation of histone H3, the expression of the cell-cycle inhibitor p21 waf1 , and the myofibroblast markers a-smooth muscle actin (a-SMA) and collagens I and III were determined by Western blotting, quantitative RT-PCR, immunofluorescent staining, or colorimetry. SpA inhibited the proliferation of IPF or normal fibroblasts in a time-dependent and concentration-dependent manner (concentration required to achieve 50% inhibition ¼ 3.8 6 0.4 nM versus 7.8 6 0.2 nM, respectively; P , 0.05), with little cytotoxicity. Western blot analyses revealed that SpA caused a concentration-dependent increase in histone H3 acetylation, paralleling its antiproliferative effect. SpA also increased p21 waf1 expression, suggesting that direct cell-cycle regulation was the mechanism of inhibiting proliferation. Although treatment with TGF-b 1 induced myofibroblast differentiation associated with increased expression of a-SMA, collagen I and collagen III and soluble collagen release, these responses were potently inhibited by SpA. These data support the concept that bicyclic tetrapeptide HDIs merit further investigation as potential treatments for IPF.Keywords: pulmonary fibrosis; histone deacetylase inhibitor; spiruchostatin A; myofibroblast; proliferation Interstitial lung diseases (ILDs) are among the most difficult respiratory diseases to manage and treat effectively. One of the most common and important ILDs is idiopathic pulmonary fibrosis (IPF) (1), with an estimated incidence of 6.8-14 cases per 100,000, and a frequency that is slightly higher in the male population (2). It is a progressive disease that causes significant morbidity and mortality (3). The etiology of IPF is unknown, and its prognosis is as dismal as that of lung cancer (a median 2-4 years of survival from time of diagnosis) (4). Currently no effective treatment exists and, to make matters worse, available therapies that include corticosteroids and other immunosuppressive agents frequently cause unpleasant and sometimes dangerous side effects. The histologic hallmark of IPF is a heterogeneous appearance with areas of normal lung alternating with fibro...

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“…Keywords: FK228 · histone deacetylase inhibitors · natural products · spiruchostatins · total synthesis Spiruchostatins A (1) and B (2) (Figure 1), isolated from a culture broth of Pseudomonas sp. by Shin-ya et al in 2001, [3] were found to exhibit potent HDAC inhibitory activity.…”

Section: Introductionmentioning

confidence: 97%

Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5′′‐epi‐Spiruchostatin B, FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity

Narita

Kikuchi

Watanabe

et al. 2009

Chemistry A European J

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The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia-Kocienski olefination of a 1,3-propanediol-derived sulfone and a L- or D-malic acid-derived aldehyde to access the most synthetically challenging unit, (3S or 3R,4E)-3-hydroxy-7-mercaptohept-4-enoic acid, present in a D-alanine- or D-valine-containing segment; ii) a condensation of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids; and iii) a macrocyclization of a seco-acid using the Shiina method or the Mitsunobu method to construct the requisite 15- or 16-membered macrolactone. The present synthesis has established the C5'' stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell-growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure-activity relationships. It was also found that unnatural 5''-epi-spiruchostatin B shows extremely high selectivity (ca. 1600-fold) for class I HDAC1 (IC(50)=2.4 nM) over class II HDAC6 (IC(50)=3900 nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC(50) values.

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Spiruchostatins A and B, novel gene expression-enhancing substances produced by Pseudomonas sp.

Cited by 98 publications

References 10 publications

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

Spiruchostatin A Inhibits Proliferation and Differentiation of Fibroblasts from Patients with Pulmonary Fibrosis

Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5′′‐epi‐Spiruchostatin B, FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity

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