A selenium-containing selective histone deacetylase 6 inhibitor for targeted in vivo breast tumor imaging and therapy

2019 ◽  
Vol 7 (22) ◽  
pp. 3528-3536 ◽  
Author(s):  
Chu Tang ◽  
Yang Du ◽  
Qian Liang ◽  
Zhen Cheng ◽  
Jie Tian
Keyword(s):  
Breast Cancer ◽  
Histone Deacetylase ◽  
Treatment Efficacy ◽  
Breast Tumor ◽  
Tumor Imaging ◽  
Selective Inhibitor ◽  
Biodistribution Study ◽  
Histone Deacetylase 6 ◽  
Antitumor Effects

We have developed a HDAC6-selective inhibitor, SelSA, which can be utilized as a target for the detection and treatment of ERα(+) breast cancer and TNBC. The biodistribution study showed that SelSA can specifically target the breast tumor and display potent antitumor effects in vivo. This result will help to better improve the treatment efficacy against breast cancer.

In vitro evaluation of estrogenic, antiestrogenic and antitumor effects of amentoflavone

2021 ◽  
pp. 096032712199945
Author(s):  
AT Aliyev ◽  
S Ozcan-Sezer ◽  
A Akdemir ◽  
H Gurer-Orhan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Antitumor Effects ◽  
Antiestrogenic Activity ◽  
Er Positive ◽  
In Vivo Effects ◽  
Mcf 7

Apigenin, a flavonoid, is reported to act as an estrogen receptor (ER) agonist and inhibit aromatase enzyme. However, amentoflavone, a biflavonoid bearing two apigenin molecules, has not been evaluated for its endocrine modulatory effects. Besides, it is highly consumed by young people to build muscles, enhance mood and lose weight. In the present study, apigenin was used as a reference molecule and ER mediated as well as ER-independent estrogenic/antiestrogenic activity of amentoflavone was investigated. Antitumor activity of amentoflavone was also investigated in both ER positive (MCF-7 BUS) and triple-negative (MDA-MB-231) breast cancer cells and its cytotoxicity was evaluated in human breast epithelial cells (MCF-10A). Our data confirmed ER agonist, aromatase inhibitory and cytotoxic effects of apigenin in breast cancer cells, where no ER mediated estrogenic effect and physiologically irrelevant, slight, aromatase inhibition was found for amentoflavone. Although selective cytotoxicity of amentoflavone was found in MCF-7 BUS cells, it does not seem to be an alternative to the present cytotoxic drugs. Therefore, neither an adverse effect, mediated by an estrogenic/antiestrogenic effect of amentoflavone nor a therapeutical benefit would be expected from amentoflavone. Further studies could be performed to investigate its in vivo effects.

scholarly journals Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

2020 ◽  
Author(s):  
Wenbao Lu ◽  
Meicen Zhou ◽  
Bing Wang ◽  
Xueting Liu ◽  
Bingwei Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Breast Cancer Cell ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.

Young Barley Indicates Antitumor Effects in Experimental Breast Cancer In Vivo and In Vitro

2016 ◽  
Vol 68 (4) ◽  
pp. 611-621 ◽  
Author(s):  
Peter Kubatka ◽  
Martin Kello ◽  
Karol Kajo ◽  
Peter Kruzliak ◽  
Desanka Výbohová ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Effects

Dual Targeting Strategies On Histone Deacetylase 6 (HDAC6) And Heat Shock Protein 90 (Hsp90)

2021 ◽  
Vol 28 ◽  
Author(s):  
Davide Bonanni ◽  
Andrea Citarella ◽  
Davide Moi ◽  
Luca Pinzi ◽  
Elisa Bergamini ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Single Molecule ◽  
Heat Shock Protein 90 ◽  
Histone Deacetylase 6 ◽  
Small Molecular Weight ◽  
Antitumor Effects ◽  
Target Drug ◽  
Dual Inhibitors

: The design of multi-target drugs acting simultaneously on multiple signaling pathways is a growing field in medicinal chemistry, especially for the treatment of complex diseases such as cancer. Histone deacetylase 6 (HDAC6) is an established anticancer drug target involved in tumor cells transformation. Being an epigenetic enzyme at the interplay of many biological processes, HDAC6 has become an attractive target for polypharmacology studies aimed at improving therapeutic efficacy of anticancer drugs. For example, the molecular chaperone Heat shock protein 90 (Hsp90) is a substrate of HDAC6 deacetylation, and several lines of evidence demonstrate that simultaneous inhibition of HDAC6 and Hsp90 promote synergistic antitumor effects on different cancer cell lines, highlighting the potential benefits of developing a single molecule endowed with multi-target activity. This review will summarize the complex interplay between HDAC6 and Hsp90, providing also useful hints for multi-target drug design and discovery approaches in this field. To this end, crystallographic structures of HDAC6 and Hsp90 complexes will be extensively reviewed in the light of discussing binding pockets features and pharmacophore requirements and providing useful guidelines for the design of dual inhibitors. The few examples of multi-target inhibitors obtained so far, mostly based on chimeric approaches, will be summarized and put into context. Finally, the main features of HDAC6 and Hsp90 inhibitors will be compared, and ligand- and structure-based strategies potentially useful for the development of small molecular weight dual inhibitors will be proposed and discussed.

Abstract 5186: Discovery of a novel histone deacetylase 6 inhibitor that kills drug-resistant breast cancer

2019 ◽  
Author(s):  
Catríona Dowling ◽  
Eugene Dillion ◽  
Michael Hemann ◽  
Gerard Cagney ◽  
Anthony Letai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Histone Deacetylase ◽  
Drug Resistant ◽  
Histone Deacetylase 6

scholarly journals Functionalized nanoparticles with targeted antibody to enhance imaging of breast cancer in vivo

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Jesse S. Chen ◽  
Jingwen Chen ◽  
Somnath Bhattacharjee ◽  
Zhengyi Cao ◽  
Han Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Detection ◽  
Tumor Imaging ◽  
Growth Factor Receptor ◽  
Therapeutic Monitoring ◽  
Mouse Tumor ◽  
Her 2 ◽  
Epidermal Growth ◽  
Magnetic Resonance Imaging Mri

Abstract Background Targeted contrast nanoparticles for breast tumor imaging facilitates early detection and improves treatment efficacy of breast cancer. This manuscript reports the development of an epidermal growth factor receptor-2 (HER-2) specific, bi-modal, dendrimer conjugate to enhance computed tomography (CT) and magnetic resonance imaging (MRI) of HER-2-positive breast cancer. This material employs generation 5 poly(amidoamine) dendrimers, encapsulated gold nanoparticles, chelated gadolinium, and anti-human HER-2 antibody to produce the nanoparticle contrast agent. Results Testing in two mouse tumor models confirms this contrast agent’s ability to image HER-2 positive tumors. Intravenous injection of this nanoparticle in mice bearing HER-2 positive mammary tumors significantly enhances MRI signal intensity by ~ 20% and improves CT resolution and contrast by two-fold. Results by flow cytometry and confocal microscopy validate the specific targeting of the conjugate and its internalization in human HER-2 positive cells. Conclusion These results demonstrate that this nanoparticle conjugate can efficiently target and image HER-2 positive tumors in vivo and provide a basis for the development of this diagnostic tool for early detection, metastatic assessment and therapeutic monitoring of HER-2 positive cancers.

Estrogen receptor β represses breast tumor growth and angiogenesis in vivo

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10101-10101
Author(s):  
J. Hartman ◽  
K. Lindberg ◽  
J. Inzunza ◽  
J. Wan ◽  
A. Ström ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth ◽  
Angiogenic Effect

10101 Background: Estrogens are well known stimulators of breast cancer cell growth in vitro as well as in vivo. Two different estrogen receptors exist, namely estrogen receptor (ER) α and β. ERα mediates the proliferative effect of estrogen in breast cancer cells and we have earlier shown that ERβ inhibits cell-cycle progression in vitro. Estrogens are well known stimulators of in vivo breast cancer cell growth as well as angiogenesis, and the effect is mediated through ERα. The function of ERβ in this context is not well understood. Methods: We have used ERα-positive T47D breast cancer cells stably transfected with a Tet/Off regulated ERβ expression vector system. The ERβ-inducible tumor cells are studied in vitro as well as in vivo. Results: By transplanting ERβ-inducible breast cancer cells into SCID-mice, we show that ERβ inhibits tumor growth and reduces the volume of established tumors. Furthermore, we show by immunohistochemistry, that the number of blood microvessels in the tumor periphery is decreased by ERβ expression, counteracting the well-known pro-angiogenic effect of ERα. By Western blot analysis on tumor extracts, we show that the concentration of the important pro-angiogenic growth factors VEGF and bFGF, normally expressed by breast tumor cells, is decreased in the ERβ-expressing tumors compared to the normal tumors. To exclude that the observed anti-angiogenic effect is just a result of reduced tumor growth, we incubated Tet/Off regulated ERβ expressing cells in vitro, during non-hypoxic conditions. We found that the expression of ERβ leads to decreased expression of VEGF and PDGFβ at the mRNA and protein-levels. In transient transfection assays, we found estrogen-ERα mediated up regulation of VEGF, PDGFβ and bFGF-promoter activities in T47D cells, and these activities were all suppressed following co-transfection with an ERβ-expression vector. Conclusions: We conclude that ERβ inhibits growth factor expression at transcriptional level in breast cancer cells; taken together, our data indicates that ERβ inhibits growth and angiogenesis of tumors formed by T47D breast cancer cells. This makes ERβ an interesting therapeutic target in breast cancer and perhaps treatment with the newly designed ERβ-selective ligands might work as a new anti-proliferative and anti-angiogenic therapy. No significant financial relationships to disclose.

Megestrol acetate may stimulate the production of insulin-like growth factor 1 in breast tissues of women with breast cancer

2013 ◽  
Vol 13 (3) ◽  
Author(s):  
Mia Fahlén ◽  
Lars Löfgren ◽  
Eva von Schoultz ◽  
Sabine Naessén ◽  
Kjell Carlström ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Breast Tumor ◽  
Megestrol Acetate ◽  
Sex Hormone Binding Globulin ◽  
Tamoxifen Treatment ◽  
Insulin Like Growth Factor ◽  
Normal Human Breast ◽  
Breast Tissues

AbstractIn women with breast cancer who were treated with either continuous tamoxifen alone or sequential tamoxifen followed by megestrol acetate (MA), we demonstrated significant positive associations between the breast tumor estrogen receptor (ER) and an increase in serum sex hormone-binding globulin (SHBG) during tamoxifen treatment. We interpreted this as “ER uniformity” in different tissues, e.g., breast, liver. No other associations with ER were found. In the same study, the breast tumor progesterone receptor (PR) was determined. Our aim was to see if there were any associations between PR and endocrine changes during MA treatment.The breast tumor PR before treatment and serum insulin-like growth factor I (∂IGF-1), steroids, steroid-binding proteins, and insulin before and during treatment were measured in 17 postmenopausal women with breast cancer who were treated sequentially with tamoxifen 40 mg/day followed by MA 160 mg/day in alternating 3-month periods.During MA treatment periods, the levels of IGF-1 and insulin increased significantly, whereas the levels of androgens, SHBG, corticosteroid-binding globulin, and cortisol decreased significantly. Significant positive correlations were found between the PR content and increments in ∂IGF-1 but not between PR and any other endocrine change.PR expression in human liver is very weak, but malignant and normal breast tissues secrete considerable amounts of growth hormone and IGF-1 in vitro and in vivo. This activity is stimulated by progestogens. The association between PR and ∂IGF-1 may therefore reflect a direct PR-mediated action of MA on malignant and normal human breast tissues in vivo.

scholarly journals Antitumor effects of a novel histone deacetylase inhibitor NK-HDAC-1 on breast cancer

2013 ◽  
Vol 30 (1) ◽  
pp. 499-505 ◽  
Author(s):  
ZHONG-HUA LI ◽  
XIAO-BING ZHANG ◽  
XI-QIAN HAN ◽  
CONG-RAN FENG ◽  
FENG-SHAN WANG ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Antitumor Effects ◽  
Deacetylase Inhibitor
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