Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer

Tang, Chu; Li, Changhao; Zhang, Silong; Hu, Zhigang; Wu, Jun; Dong, Chune; Huang, Jian; Zhou, Hai-Bing

doi:10.1021/acs.jmedchem.5b00099

Cited by 97 publications

(84 citation statements)

References 46 publications

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“…Numerous chemical hybrid molecules containing both HDACi activities and an additional anticancer module are under development, dual targeting HDACs and estrogen receptor (ER) (Tang et al 2015), retinoid X receptor (RXR) (Wang et al 2015), topoisomerase I/II (Guerrant et al 2013), 1α, 25- vitamin D (Lamblin et al 2010), oestrogen receptor (Gryder et al 2013), receptor tyrosine kinases (RTK) (Zhang et al 2013), tubulin (Zhang et al 2015b) or DNA methyltransferase (Shukla et al 2015), potentially leading to a rational efficacy in cancer therapy. Additionally, the hybrid of a nitric oxide (NO) donor and an histone deacetylase inhibitor has been developed and displayed outstanding antiproliferative activity in tumor cells (Duan et al 2015).…”

Section: Anticancer Effect Of Hdac Inhibitorsmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

957

765

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Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Post-translational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling and nuclear architecture. Histone acetylation, a well-studied post-translational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous non-histone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.

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Section: Anticancer Effect Of Hdac Inhibitorsmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

957

765

View full text Add to dashboard Cite

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“…48–50 In particular, compounds that target multiple relevant mechanisms for single diseases may be more effective than compounds with single mechanisms of action. 48,49 …”

Section: Resultsmentioning

confidence: 99%

Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules

et al. 2016

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Three scaffolds with inhibitory activity against the heat shock protein 70 (Hsp70) family of chaperones have been found to enhance the degradation of the microtubule associated protein tau in cells, neurons, and brain tissue. This is important because tau accumulation is linked to neurodegenerative diseases including Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Here, we expanded upon this study to investigate the anti-tau efficacy of additional scaffolds with Hsp70 inhibitory activity. Five of the nine scaffolds tested lowered tau levels, with the rhodacyanine and phenothiazine scaffolds exhibiting the highest potency as previously described. Because phenothiazines also inhibit tau aggregation in vitro, we suspected that this activity might be a more accurate predictor of tau lowering. Interestingly, the rhodacyanines did inhibit in vitro tau aggregation to a similar degree as phenothiazines, correlating well with tau-lowering efficacy in cells and ex vivo slices. Moreover, other Hsp70 inhibitor scaffolds with weaker tau-lowering activity in cells inhibited tau aggregation in vitro, albeit at lower potencies. When we tested six well-characterized tau aggregation inhibitors, we determined that this mechanism of action was not a better predictor of tau-lowering than Hsp70 inhibition. Instead, we found that compounds possessing both activities were the most effective at promoting tau clearance. Moreover, cytotoxicity and PAINS activity are critical factors that can lead to false-positive lead identification. Strategies designed around these principles will likely yield more efficacious tau-lowering compounds.

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“…Accumulating evidence suggests that using natural or dietary agents as therapies for cancer, particularly in combination with conventional therapies, may provide clinicians with new options with which they can manage their patients [41-43]. Several epidemiological and preclinical studies have highlighted the potential benefits of using flavonoids for cancer prevention.…”

Section: Discussionmentioning

confidence: 99%

Quercetin Inhibits Cell Migration and Invasion in Human Osteosarcoma Cells

Lan

Wang

Fan

et al. 2017

Cell Physiol Biochem

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Background/Aims: Osteosarcoma is a malignant tumor associated with high mortality; however, no effective therapies for the disease have been developed. Several studies have focused on elucidating the pathogenesis of osteosarcoma and have aimed to develop novel therapies for the disease. Quercetin is a vital dietary flavonoid that has been shown to have a variety of anticancer effects, as it induces cell cycle arrest, apoptosis, and differentiation and is involved in cell adhesion, metastasis and angiogenesis. Herein, we aimed to investigate the effects of quercetin on osteosarcoma migration and invasion in vitro and in vivo and to explore the molecular mechanisms underlying its effects on osteosarcoma migration and invasion. Methods: Cell viability, cell cycle activity and cell apoptosis were measured using CCK-8 assay and flow cytometry, and cell migration and invasion were evaluated by wound healing and transwell assays, respectively. The mRNA and protein expression levels of several proteins of interest were assessed by real-time quantitative PCR and western blotting, respectively. Moreover, a nude mouse model of human osteosarcoma lung metastasis was established to assess the anti-metastatic effects of quercetin in vivo. Results: We noted no significant differences in cell cycle activity and apoptosis between HOS and MG63 cells and control cells. Treatment with quercetin significantly attenuated cell migration and invasion in HOS and MG63 cells compared with treatment with control medium. Moreover HIF-1α, VEGF, MMP2, and MMP9 mRNA and protein expression levels were significantly downregulated in HOS cells treated with quercetin compared with HOS cells treated with controls. Additionally, treatment with quercetin attenuated metastatic lung tumor formation and growth in the nude mouse model of osteosarcoma compared with treatment with controls. Conclusion: Our findings regarding the inhibitory effects of quercetin on cell migration and invasion suggest that quercetin may have potential as a therapy for human osteosarcoma.

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Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer

Cited by 97 publications

References 46 publications

HDACs and HDAC Inhibitors in Cancer Development and Therapy

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules

Quercetin Inhibits Cell Migration and Invasion in Human Osteosarcoma Cells

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