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DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers. KU-0060648 is a dual
PURPOSE: Inhibition of DNA repair is emerging as a new therapeutic strategy for cancer treatment. One promising target is DNA-PK, a pivotal kinase in double-strand break repair. The purpose of this study was to further characterise the activity of the DNA-PK inhibitor NU7441, giving some new insights into the biology of DNA-PK.METHODS: We used NU7441, a potent DNA-PK inhibitor, to evaluate potenti
BACKGROUND: The molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic.METHODS: We tested the efficacy of a novel mitochondrial-targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. Th
Inflammatory mediators present in the tumor milieu may promote cancer progression and are considered promising targets of novel biological therapies. We previously reported that the marine antitumor agent trabectedin, approved in Europe in 2007 for soft tissue sarcomas and in 2009 for ovarian cancer, was able to downmodulate the production of selected cytokines/chemokines in immune cells. Patients
Glucosinolates (GLs), natural compounds extracted from Brassicaceae and precursors of isothiocyanates (ITCs), have been studied in the last decades mostly due to their chemopreventive activity and, more recently, for their potential use as novel chemotherapeutics. The aim of the present study was to investigate the in vitro and in vivo activity of glucomoringin (GMG), an uncommon member of the GLs
Differentiation is a complex set of events that can be blocked by rearrangements of regulatory genes producing fusion proteins with altered properties. In the case of myxoid liposarcoma (MLS) tumors, the causative abnormality is a fusion between the CHOP transcription factor and the FUS or EWS genes. CHOP belongs to and is a negative regulator of the large CAAT/enhancer binding protein family whos
The p73 locus gene has a complex structure encoding a plethora of isoforms. The different DeltaN truncated isoforms of p73 may exert different activities depending on the cellular context. The beta isoform of DeltaNp73 seems to have a particular pattern of action even if its role in cell cycle and mitosis is still under investigation. To gain further knowledge of DeltaNp73beta's function, we inves
Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular a
PURPOSE: After DNA damage, checkpoints pathways are activated in the cells to halt the cell cycle, thus ensuring repair or inducing cell death. To better investigate the role of checkpoint kinase 1 (Chk1) in cellular response to different anticancer agents, Chk1 was knocked down in HCT-116 cell line and in its p53-deficient subline by using small interfering RNAs (siRNA).EXPERIMENTAL DESIGN: Chk1
Trabectedin (ET-743, Yondelis) is a natural marine compound with antitumour activity currently undergoing phase II/III clinical trials. The mechanism of the drug's action is still to be defined, even though it has been clearly demonstrated the key role of Nucleotide Excision Repair (NER). To get further insights into the drug's mode of action, we studied the involvement of the DNA-double strand br
TO-PRO-3 iodide (TP3), a monomeric cyanine nucleic acid stain with a peak absorbance at 642 nm and emission at 661 nm, is best excited by a helium-neon (HeNe) laser (633nm). It was tested in monocytes and different cell lines under conditions of different fixatives, dye concentrations, labeling kinetics and RNAse concentrations for mono-, bi- and tri-parametric flow cytometric cell cycle analysis
OBJECTIVES: Trabectedin (ET-743, Yondelis) is a natural marine product, with antitumour activity, currently in phase II/III clinical trials. Previous studies have shown that cells hypersensitive to ultraviolet (UV)-rays because of nucleotide excision repair (NER) deficiency, were resistant to trabectedin. The purpose of this study was to investigate whether this resistance was associated with diff
Drug design based on the structure of specific enzymes playing a role in carcinogenesis, e.g. tyrosine kinases, has been successful at identifying novel effective anticancer drugs. In contrast, no success has been achieved in drug design attempts, in which transcription factors or DNA-transcription factor complexes involved in the pathogenesis of human neoplasms were targeted. This failure is like
The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid] and CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) are promising anticancer agents. We compared the retinoic acid receptor (RAR) trans-activating properties of the two RRMs and all-trans-retinoic acid (ATRA). ST1926 and CD437 are better RARgamma agonists than ATRA. We
This paper illustrates some biochemical and pharmacological properties of two natural marine products such as trabectedin (ET-743, Yondelis) and aplidine. Trabectedin has shown clinical antitumor activity in refractory soft tissue sarcoma and ovarian cancer. The lack of cross resistance of trabectedin with other chemotherapeutic drugs is presumably related to its peculiar mode of action, that seem
In the near future, the number of connected mobile devices and data-rates are expected to dramatically increase. Demands exceed the capability of the currently deployed (4G) wireless communication systems. Development of 5G systems is aiming for higher data-rates, better coverage, backward compatibility, and conforming with “green communication” to lower energy consumption. Massive Multiple-Input
Remains of a basilican round church were discovered in 1877–78 in Tønsberg, Norway, and identified as the Premonstratensian monastery church of Saint Olav. The round church has been interpreted as fortified with several floors using Nylars on Bornholm in Denmark as a model – or as symbolic copy of Holy Sepulchre in Jerusalem, although Templar churches have also been mentioned as models. The church
In the presented paper experimental and numerical analyses are made of the failure due to blister formation in moist packaging material when exposed to excessive heating. The basic concept of the experimental analysis is to expose a package material to a hot air jet and measure the time until the material experience internal failure. For the numerical analysis, a triphasic macroscale hybrid mixtur
A growing set of policies involve transfers conditioned upon socially desired actions, such as attending school or conserving forest. However, given a desire to maximize the impact of limited funds by avoiding transfers that do not change behavior, typically some potential recipients are excluded on the basis of their characteristics, their actions or at random. This paper uses a laboratory experi
Råttan är en däggdjursart med en kort dräktighetstiden och föds därför mycket omogen. Den är vid födelsen naken, blind och döv och är helt beroende av sin moder för många funktioner, såsom näringstillförsel, termoreglering, urinering och tarmtömning. Under diperioden är råttans mag-tarmsystem och matsmältning helt anpassad till modersmjölkdieten. Bland annat är tarmens barriärfunktion omogen, vilkThe rat, as an altritial species, is born with an immature gastrointestinal tract and intestinal barrier function, which is highly absorptive to milk-borne bioactive molecules that can pass undigested and reach the general circulation of the suckling newborn. This passage occurs by the neonatal-Fc-receptor (FcRn) binding and trancytosis of immunoglobulin G in the proximal small intestine (SI) and
