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DOT1L, a specific H3K79 methyltransferase, has a tumour‐promoting role in various cancers, including triple‐negative breast cancer (TNBC). However, the molecular mechanism by which the deregulated DOT1L promotes cancer progression is unclear. Herein, we show that a significantly higher basal level of DOTL1 strongly correlates with MTDH, an oncogene, in clinical TNBC patient cohorts and mediates TNBC progression by enhancing MTDH‐induced angiogenesis. In parallel, severe combined immunodeficiency mice‐bearing MDA‐MB‐231 cells with MTDH‐Wt or MTDHΔ7 (spliced isoform of MTDH) overexpression constructs showed enhanced blood vessel formations at the tumour site in comparison with control groups. Selective inhibition of DOT1L by EPZ004777, a specific DOT1L inhibitor, or siDOT1L, significantly impaired MTDH‐induced proliferation, invasion and angiogenic markers expression in TNBC cells. ChIP assay revealed that Dot1L promotes MTDH‐Wt/Δ7 transcription by increasing H3K79me3 levels on its promoter. Dot1L depletion reversed this effect. Mechanistically, DOT1L‐induced MTDH caused enhanced nuclear factor kappa B (NF‐κB) occupancy on the hypoxia‐inducible factor1α (HIF1α) promoter and increased its transcription, leading to elevated levels of proangiogenic mediators in TNBC cells. Moreover, the condition media obtained from MDA‐MB‐231 cells stably expressing either MTDH‐Wt or MTDHΔ7 treated with EPZ004777 or Bay‐11‐7082 (NF‐κB inhibitor) or FM19G11 (HIF1α inhibitor) significantly inhibited MTDH‐induced tube formation in human umbilical vein endothelial cells, rat aortic ring sprouting and vessel formations by chick chorioallantoic membrane assay mimicking physiological angiogenic vasculature. Collectively, our findings reveal a novel epigenetic regulation of MTDH by DOTL1, which drives angiogenesis, and that the therapeutic disruption of the DOT1L‐MTDH‐NF‐κB‐HIF1α axis may have usefulness in the management of TNBC. [ABSTRACT FROM AUTHOR]

In an effort to design and develop efficient anticancer agents here, we report the synthesis, anticancer activity and molecular docking studies of new 3‐(2‐(5 amino‐3‐aryl‐1H‐pyrazol‐1‐yl)thiazol‐4‐yl)‐2H‐chromen‐2‐ones. The target products were synthesized via a facile one pot multicomponent approach by utilizing various substituted 3‐(2‐bromoacetyl)coumarins(1 a‐j), thiosemicarbazide (2) and benzoylacetonitriles (3 a–c) with excellent yields. All the synthesized compounds were characterized by physical and analytical methods (IR, 1H NMR, 13C NMR and Mass spectra) and screened for their anti cancer property against five human cancer cell lines [L1210, CEM, DU‐145, HeLa, and MCF‐7]. Among the tested compounds, 6‐diethylamino substituted compound 4 k exhibited excellent potency against tested cancer cell lines, whereas 6,8‐Ditert‐butyl substituted compound 4 j shown promising activity against DU‐145 and MCF‐7 cancer cell lines with IC50 values of 7±1 and 9±6 μM. Molecular docking study was carried out in order to understand the most plausible binding site interactions of the compounds with human Epidermal growth factor receptor (EGFR). [ABSTRACT FROM AUTHOR]

In this study we explored the microRNAs responsible for the regulation of PAI-1 during LPS-stimulated inflammation in human aortic endothelial cells and subsequently studied the effect of a newly synthesized mitochondria-targeted esculetin (Mito-Esc) that was shown for its anti-atherosclerotic potential, in modulating PAI-1 levels and its targeted miRs during angiotensin-II-induced atherosclerosis in ApoE−/− mice. LPS-stimulated PAI-1 was accompanied with an upregulation of miR-19b and down-regulation of miR-30c. These effects of LPS on PAI-1 were reversed in the presence of both parent esculetin and Mito-Esc. However, the effect of Mito-Esc was more pronounced in the regulation of PAI-1. In addition, LPS-stimulated PAI-1 expression was significantly decreased in cells treated with Anti-miR-19b, thereby suggesting that miR-19b co-expression plays a key role in PAI-1 regulation. The results also show that incubation of cells with Stattic, an inhibitor of STAT-3, inhibited LPS-stimulated PAI-1 expression. Interestingly, knockdown of SIRT3, a mitochondrial biogenetic marker, enhanced PAI-1 levels via modulation of miR-19b and -30c. Mito-Esc treatment significantly inhibited Ang-II-induced PAI-1, possibly via altering miR-19b and 30c in ApoE−/− mice. The association between PAI-1, miR-19b and -30c were further confirmed in plasma and microparticles isolated from patients suffering from acute coronary syndrome of various degrees. Taken together, LPS-induced PAI-1 involves co-expression of miR-19b and down regulation of miR-30c, and Mito-Esc treatment by modulating miR-19b and miR-30c through SIRT3 activation, inhibits PAI-1 levels that, in part, contribute to its anti-atherosclerotic effects. Moreover, there exists a strong positive correlation between miR-19b and PAI-1 in patients suffering from ST-elevated myocardial infarction. [ABSTRACT FROM AUTHOR]

Recent studies have highlighted the involvement of metadherin ( MTDH), an oncogenic protein, in promoting cancer progression, metastasis and chemoresistance in many cancers including mammary carcinomas. However, the molecular regulation of MTDH is still not completely understood. In this study we document that AMP activated protein kinase ( AMPK) activation-induced anti-proliferative effects are, in part, mediated by inhibiting MTDH expression in MDA- MB-231 and BT-549 triple negative breast cancer ( TNBC) cells. 5-Aminoimidazole-4-carboxamide ribonucleotide ( AICAR), an AMPK activator, caused growth arrest, inhibition of migration and invasion of TNBC cells. Intriguingly, AICAR or metformin treatment resulted in significant downregulation of MTDH expression via inhibiting c-Myc expression. In contrast, treatment of cells with compound C, an inhibitor of AMPK, increased both c-Myc and MTDH expressions in TNBC cells. Also, AMPK activation caused increased glycogen synthase kinase 3β ( GSK3β) activity by inhibiting the inactive phosphorylation at Ser9, on the one hand, and activation of sirtuin1 ( SIRT1) by inhibiting Ser47 phosphorylation, as evidenced by deacetylation of p53, on the other hand. Moreover, AMPK-induced GSK3β and SIRT1 activities were found to be responsible for inhibiting c-Myc-mediated upregulation of MTDH, as LiCl (an inhibitor of GSK3β) and EX-527 (an inhibitor of SIRT1) reversed AICAR-mediated downregulation of c-Myc and MTDH expressions. Similar results were observed with si SIRT1 treatment. Furthermore, AICAR and EX-527 treatments caused increased cell death under MTDH-depleted conditions. Finally, we uncovered a novel regulation of MTDH expression and showed that AMPK activation by inducing GSK3β and SIRT1 downregulates MTDH expression via inhibiting c-Myc in TNBC cells. [ABSTRACT FROM AUTHOR]

The 3-amino-6-(trifluoromethyl)furo[2,3- b]pyridine-2-carbohydrazide ( 5) was prepared from 3-cyano-6-trifluoromethyl-2(1 H)pyridone ( 2) in series of steps via selective , followed by reaction with hydrazine hydrate. The 2-carbohydrazide ( 5) was further reacted with aliphatic acids under different reaction temperatures to form a series of novel N-acylfuro[2,3- b]pyridine-2-carbohydrazide ( 6) and pyrido[3′,2′:4,5]furo[3,2- d]pyrimidine derivatives ( 7). All the compounds 6 and 7 were screened for cytotoxic activity against breast carcinoma MD Anderson-Metastatic Breast (MDA-MB) 231 (aggressive) cell lines at 10 µM concentration. Compounds 6a, 6b, and 6c showed promising activity. [ABSTRACT FROM AUTHOR]

Accumulating evidence from in vitro, in vivo, clinical and epidemiological studies shows promising results for the use of statins against many cancers including breast carcinoma. However, the molecular mechanisms responsible for the anti-proliferative and anti-invasive properties of statins still remain elusive. In this study, we investigated the involvement of nitric oxide, iron homeostasis and antioxidant defence mechanisms in mediating the anti-proliferative and anti-invasive properties of hydrophobic statins in MDA-MB-231, MDA-MB-453 and BT-549 metastatic triple negative breast cancer cells. Fluvastatin and simvastatin significantly increased cytotoxicity which was reversed with mevalonate. Interestingly, fluvastatin downregulated transferrin receptor (TfR1), with a concomitant depletion of intracellular iron levels in these cells. Statin-induced effects were mimicked by geranylgeranyl transferase inhibitor (GGTI-298) but not farnesyl transferase inhibitor (FTI-277). Further, it was observed that TfR1 downregulation is mediated by increased nitric oxide levels via inducible nitric oxide synthase (iNOS) expression. NOS inhibitors (asymmetric dimethylarginine and 1400W) counteracted and sepiapterin, a precursor of tetrahydrobiopterin, exacerbated statin-induced depletion of intracellular iron levels. Notably, fluvastatin increased manganese superoxide dismutase (by repressing the transcription factor DNA damage-binding protein 2), catalase and glutathione which, in turn, diminished H2O2 levels. Fluvastatininduced downregulation of TfR1, matrix metalloproteinase-2, -9 and inhibition of invasion were reversed in the presence of aminotriazole, a specific inhibitor of catalase. Finally, we conclude that fluvastatin, by altering iron homeostasis, nitric oxide generation and antioxidant defence mechanisms, induces triple negative breast cancer cell death. [ABSTRACT FROM AUTHOR]