Breast cancer accounts for 25% of all types of cancer in women, and triple negative breast cancer (TNBC) comprises around 15~20% of breast cancers. Conventional chemotherapy and radiation are the ...primary systemic therapeutic strategies; no other FDA-approved targeted therapies are yet available as for TNBC. TNBC is generally characterized by a poor prognosis and high rates of proliferation and metastases. Due to these aggressive features and lack of targeted therapies, numerous attempts have been made to discover viable molecular targets for TNBC. Massive cohort studies, clinical trials, and in-depth analyses have revealed diverse molecular alterations in TNBC; however, controversy exists as to whether many of these changes are beneficial or detrimental in caner progression. Here we review the complicated tumorigenic processes and discuss critical findings and therapeutic trends in TNBC with a focus on promising therapeutic approaches, the clinical trials currently underway, and potent experimental compounds under preclinical and evaluation.
Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers despite a relatively low incidence. Angiogenesis, one of the hallmarks of cancer, is essential for the pathogenesis of ...EOC, which is related to the induction of angiogenic factors. We found that ELF3 was highly expressed in EOCs under hypoxia and functioned as a transcription factor for IGF1. The ELF3‐mediated increase in the secretion of IGF1 and VEGF promoted endothelial cell proliferation, migration, and EOC angiogenesis. Although this situation was much exaggerated under hypoxia, ELF3 silencing under hypoxia significantly attenuated angiogenic activity in endothelial cells by reducing the expression and secretion of IGF1 and VEGF. ELF3 silencing attenuated angiogenesis and tumorigenesis in ex vivo and xenograft mouse models. Consequently, ELF3 plays an important role in the induction of angiogenesis and tumorigenesis in EOC as a transcription factor of IGF1. A detailed understanding of the biological mechanism of ELF3 may both improve current antiangiogenic therapies and have anticancer effects for EOC.
Synopsis
The hypoxic microenvironment of rapidly growing ovarian cancer upregulates the transcription factor ELF3 in the tumor cells. ELF3 directly promotes IGF1 transcription, thereby promoting vascular sprouting, proliferation, and migration of endothelial cells, leading to angiogenesis.
ELF3 is a transcription factor that induces angiogenesis by transcriptionally increasing IGF1 expression.
Hypoxia enhances the effect of ELF3 on angiogenesis.
ELF3 depletion in the ovarian cancer cells attenuates angiogenesis and tumorigenesis ex vivo and in xenograft models.
The hypoxic microenvironment of rapidly growing ovarian cancer upregulates the transcription factor ELF3 in the tumor cells. ELF3 directly promotes IGF1 transcription, thereby promoting vascular sprouting, proliferation, and migration of endothelial cells, leading to angiogenesis.
Rho is a general transcription termination factor in bacteria, but many aspects of its mechanism of action are unclear. Diverse models have been proposed for the initial interaction between the RNA ...polymerase (RNAP) and Rho (catch-up and stand-by pre-terminational models); for the terminational release of the RNA transcript (RNA shearing, RNAP hyper-translocation or displacing, and allosteric models); and for the post-terminational outcome (whether the RNAP dissociates or remains bound to the DNA). Here, we use single-molecule fluorescence assays to study those three steps in transcription termination mediated by E. coli Rho. We find that different mechanisms previously proposed for each step co-exist, but apparently occur on various timescales and tend to lead to specific outcomes. Our results indicate that three kinetically distinct routes take place: (1) the catch-up mode leads first to RNA shearing for RNAP recycling on DNA, and (2) later to RNAP displacement for decomposition of the transcriptional complex; (3) the last termination usually follows the stand-by mode with displacing for decomposing. This three-route model would help reconcile current controversies on the mechanisms.
(
E
)-3-(3-(4-((3-Carbamoylbenzyl)oxy)-3-iodo-5-methoxyphenyl) acryloyl)benzamide (
A6
) was found to be a potent p300 inhibitor (IC
50
= 870 nM) showing a similar binding mode to that of acetyl-CoA, ...a p300 substrate, and effective anti-fibrotic activity in both TGF-β1-stimulated lung fibroblast cells and bleomycin-induced
in vivo
lung fibrosis mice.
Using a field-based design approach, we systematically identified a novel potent p300 inhibitor,
A6
, with effective anti-fibrotic activity and favorable drug-like properties.
In this study, we assessed the precision and trueness of dental models printed with 3-dimensional (3D) printers via different printing techniques.
Digital reference models were printed 5 times using ...stereolithography apparatus (SLA), digital light processing (DLP), fused filament fabrication (FFF), and the PolyJet technique. The 3D printed models were scanned and evaluated for tooth, arch, and occlusion measurements. Precision and trueness were analyzed with root mean squares (RMS) for the differences in each measurement. Differences in measurement variables among the 3D printing techniques were analyzed by 1-way analysis of variance (α = 0.05).
Except in trueness of occlusion measurements, there were significant differences in all measurements among the 4 techniques (P <0.001). For overall tooth measurements, the DLP (76 ± 14 μm) and PolyJet (68 ± 9 μm) techniques exhibited significantly different mean RMS values of precision than the SLA (88 ± 14 μm) and FFF (99 ± 14 μm) techniques (P <0.05). For overall arch measurements, the SLA (176 ± 73 μm) had significantly different RMS values than the DLP (74 ± 34 μm), FFF (89 ± 34 μm), and PolyJet (69 ± 18 μm) techniques (P <0.05). For overall occlusion measurements, the FFF (170 ± 55 μm) exhibited significantly different RMS values than the SLA (94 ± 33 μm), DLP (120 ± 28 μm), and PolyJet (96 ± 33 μm) techniques (P <0.05). There were significant differences in mean RMS values of trueness of overall tooth measurements among all 4 techniques: SLA (107 ± 11 μm), DLP (143 ± 8 μm), FFF (188 ± 14 μm), and PolyJet (78 ± 9 μm) (P <0.05). For overall arch measurements, the SLA (141 ± 35 μm) and PolyJet (86 ± 17 μm) techniques exhibited significantly different mean RMS values of trueness than DLP (469 ± 49 μm) and FFF (409 ± 36 μm) (P <0.05).
The 3D printing techniques showed significant differences in precision of all measurements and in trueness of tooth and arch measurements. The PolyJet and DLP techniques were more precise than the FFF and SLA techniques, with the PolyJet technique having the highest accuracy.
•The PolyJet technique provides the greatest trueness and precision.•Accuracy of 3-dimensional printers differs in the sizes of print outcomes.•Three-dimensional printing techniques may be used for orthodontic purposes.
We developed a new exercise method called the submandibular push exercise that can strengthen the suprahyoid muscle by inducing only the motion of the hyoid bone without neck flexion. In this study, ...we aimed to investigate and compare the muscle activity of the suprahyoid and infrahyoid muscles in the course of performing three different swallowing exercises. Twenty healthy participants and fifteen patients with dysphagia were recruited. Each participant consecutively performed three exercises: Shaker, CTAR, and submandibular push exercises. To investigate muscle activation, surface electromyography was performed on the suprahyoid, infrahyoid, and SCM muscles, during the exercises. Root mean square (RMS) was measured. In healthy participants, the submandibular push exercise showed a significantly higher RMS value in the suprahyoid and infrahyoid muscles than the Shaker and CTAR exercises using repeated ANOVA with Tukey's post hoc test (p < 0.05). In patients with dysphagia, the submandibular push and Shaker exercises showed significantly higher RMS value in the suprahyoid and infrahyoid muscles than the CTAR exercise. However, no significant difference was found between the submandibular push and Shaker exercises. In both healthy and patients with dysphagia, the mean RMS values of the SCM muscles during the submandibular push exercise were significantly lower than those during the Shaker exercise using repeated ANOVA with Tukey's post hoc test (p < 0.05). In conclusion, considering the relatively superior selectiveness in suprahyoid and infrahyoid muscle contraction, the submandibular push exercise using visual feedback from pressure sensor could be an efficient supplementary exercise to the conventional swallowing muscle exercises. However, further studies may be necessary to confirm the improvement in swallowing difficulty.
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease with a poor prognosis similar to that of malignancy. The causes of IPF are not clearly known, and there is no ...effective therapy to date. In this study, the natural compound plumbagin, which was isolated from
root extract, was screened for p300 inhibitory activity. Plumbagin specifically inhibited the activity of p300 toward histone acetyltransferases. Plumbagin treatment significantly suppressed transforming growth factor-
-induced profibrotic target-gene expression and proliferation of fibroblast cell lines. Moreover, plumbagin significantly inhibited bleomycin-induced pulmonary fibrosis in mice. Taken together, these data demonstrate the inhibitory effects of plumbagin on lung fibrosis and its promise as a therapeutic agent for IPF.
Heat Shock Protein 27 (HSP27) is a member of small heat shock proteins with a highly-conserved α-crystalline domain. It inhibits aggregation of damaged proteins through a complex structural systems ...of phosphorylation-dependent oligomerization and self-assembly. It has been demonstrated that HSP27 is involved in a variety of pathophysiological pathways with negative or positive protective activities. In this study, we synthesized six chromone analogs possessing thiiran-2-ylmethoxy or oxyran-2-ylmethoxy substituents and evaluated their biological activities against HSP27 protein. Compounds YK598-2, J4 and J2 induced significant abnormal HSP27 dimer formation in NCI-H460, a human lung cancer cell line. In synergistic anticancer activity test, the compounds effectively producing abnormal HSP27 cross-linking remarkably enhanced the antiproliferative activity of 17-AAG, a HSP90 inhibitor. Target specificity test using the HSP27-silenced cells (shHSP27) showed that compounds YK598-2, J4, and J2 significantly lost their cross-linking activity only under conditions when HSP27 was deprived of. In the evaluation of cancer cell sensitization with cisplatin, cisplatin-induced lung cancer cell growth inhibition was sensitized with statistical significance by J4 and J2 as compared to compound alone treatment. These results suggest that abnormal HSP27 dimerization can be an efficient control point for cancer cell proliferation and chromone compounds might have potential as anticancer agents that modulate abnormal HSP27 dimerization.
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•J2 induced significant abnormal HSP27 dimer formation in NCI-H460.•J2 remarkably enhanced the antiproliferative activity of 17-AAG.•J2 significantly lost cross-linking activity in HSP27-silenced cells (shHSP27).•J2, a chromone analogue, might have potential as anticancer agents that modulate abnormal HSP27 dimerization.
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•ELF3-MED23 hotspot was efficiently deciphered by using customized small molecules.•ELF3-MED23 PPI depends on specific H-bondings to upregulate HER2 expression.•PPI inhibitory ...activity of YK1 was specific to ELF3-MED23.•YK1-mediated specific H-bond interruption induces promising anticancer activities.•Anticancer effect of YK1 was even significant against trastuzumab-refractory clones.•YK1 held highly drug-like properties showing favorable PK profile.
HER2 overexpression induces cancer aggression and frequent recurrences in many solid tumors. Because HER2 overproduction is generally followed by gene amplification, inhibition of protein–protein interaction (PPI) between transcriptional factor ELF3 and its coactivator MED23 has been considered an effective but challenging strategy.
This study aimed to determine the hotspot of ELF3-MED23 PPI and further specify the essential residues and their key interactions in the hotspot which are controllable by small molecules with significant anticancer activity.
Intensive biological evaluation methods including SEAP, fluorescence polarization, LC-MS/MS-based quantitative, biosensor, GST-pull down assays, and in silico structural analysis were performed to determine hotspot of ELF3-MED23 PPI and to elicit YK1, a novel small molecule PPI inhibitor. The effects of YK1 on possible PPIs of MED23 and the efficacy of trastuzumab were assessed using cell culture and tumor xenograft mouse models.
ELF3-MED23 PPI was found to be specifically dependent on H-bondings between D400, H449 of MED23 and W138, I140 of ELF3 for upregulating HER2 gene transcription. Employing YK1, we confirmed that interruption on these H-bondings significantly attenuated the HER2-mediated oncogenic signaling cascades and exhibited significant in vitro and in vivo anticancer activity against HER2-overexpressing breast and gastric cancers even in their trastuzumab refractory clones.
Our approach to develop specific ELF3-MED23 PPI inhibitor without interfering other PPIs of MED23 can finally lead to successful development of a drug resistance-free compound to interrogate HER2 biology in diverse conditions of cancers overexpressing HER2.
5-Hydroxy-2-phenyl-7-(thiiran-2-ylmethoxy)-4
H
-chromen-4-one (compound
52
) was found as a DNA non-intercalative topo II specific catalytic inhibitor by targeting its ATP-binding domain. Showing ...changes in interaction with Mg
2+
, it exhibited highly selective properties against the α-isoform with less toxicity, unlike other topo II poisons, such as etoposide.
Compound
52
exhibited highly topo IIα-selective properties as an ATP competitive catalytic inhibitor with less toxicity, unlike topo II poisons.
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