Expression of Integrins, Anchorage Dependent Apoptosis and Invasiveness of Multidrug Resistant Human Breast Carcinoma Cells

The aim of the study was to investigate the role of integrins in anchorage dependent apoptosis (anoikis) and in vitro invasion of human breast cancer cell line MCF-7 and its multidrug resistant subline MCF-7Dox. Acquisition of MDR was associated with markedly decreased expression of collagen specific a2ß1 and avß3 integrins, laminin specific a3ß1 and a6ß1 receptors and dramatic up-regulation of fibronectin specific a5ß1 integrin. The MDR subline was substantially more resistant to anoikis than their wild type counterparts. Furthermore, MCF-7Dox cells secreted MMP-9 collagenase and invaded Matrigel. We demonstrate for the first time that stimulation of ß1 integrin signaling strongly sensitizes MCF-7 cells to anoikis

Secondary Electron Spectral Changes of Irradiated Gold Nanoparticle Caused By PEGylation

Gold nanoparticles attract attention for the use in radiation therapy of tumors due to the ability to enhance the efficacy of ionizing radiation. The magnitude of the radiosensitizing effect depends on the parameters of the nanoparticle, in particular on the modification of the surface. In the present work, the spectrum of secondary particles generated in a gold nanoparticle virtually irradiated with 60Со gamma rays as a result of surface modification by a polyethylene glycol shell was studied. The Mont eCarlo calculations revealed that modification of the nanoparticle’s surface changes the spectrum of secondary particles. The most robust was the loss in low-energy electrons (51%) whereas the yield of Compton electrons increased by 1.27 times. At the same time, no statistically significant changes were observed in the spectrum of secondary photons and photoelectrons. Simulation of the formation and distribution of secondary electron radiation makes it possible to evaluate the parameters important for the rational design of antitumor nanoradiosensitizers based on chemical elements with a high atomic number. Keywords: gold nanoparticles, radiosensitizers, Monte-Carlo simulation, Geant4, radiation therapy, malignant tumors

Partial restoration of the actin cytoskeleton in transformed Syrian hamster fibroblasts selected for low levels of ‘typical’ multidrug resistance

AbstractTwo independent colchicine (CLC)-resistant sublines of Rous sarcoma virus-transformed Syrian hamster flbroblasts were isolated. Each subline represented variants with 11- and 12.4-fold resistance, respectively, their 23- and 23.7-fold resistant descendants, as well as variants cultured in CLC-free medium for 10 months without loss of resistance. All variants demonstrated ‘typical’ multidrug resistance. The parental cells contained actin in dispersed form, as determined by rhodamine-phalloidin staining. In contrast, already in 11- and 12.4-fold resistant sublines up to 30% of cells demonstrated restored stress fibers. Cultivation in CLC-free medium leads to the accumulation of cells with a partially restored actin cytoskeleton. Putative mechanisms of up-regulation of stress fiber assembly in cells with P-glycoprotein-mediated multidrug resistance are discussed

The role of a2ß1 integrin in anchorage dependent apoptosis of breast carcinoma and hepatoma cells

The role of collagen specific a2ß1 integrin in anchorage dependent apoptosis (anoikis) was investigated. Stimulation of a2ß1 signaling with immobilized anti-a2 antibody markedly sensitized human MCF-7 breast carcinoma and HepG2 hepatoma cells to anoikis. Accordingly, down-regulation of a2ß1 by a2-specific siRNA decreased the percentage of cells undergoing anoikis. These results for the first time provide direct evidence that a2ß1 receptor can transduce the signal to promote death in matrix deprived cells

Синтез, изучение цитотоксических свойств и гемолитической активности катионных глицеролипидов алкильного типа.

The synthesis of new cationic ether glycerolipids, non-phosphoros analogues of edelfosine. Are investigated cytotixic properties and hemolytic activity of the synthesized substances.Синтезированы новые катионные глицеролипиды с простой эфирной связью – бесфосфорные аналоги эдельфозина. Изучены их цитотоксические свойства и гемолитическая активность

Identifying Cancers Impacted by CDK8/19

CDK8 and CDK19 Mediator kinases are transcriptional co-regulators implicated in several types of cancer. Small-molecule CDK8/19 inhibitors have recently entered or are entering clinical trials, starting with breast cancer and acute myeloid leukemia (AML). To identify other cancers where these novel drugs may provide benefit, we queried genomic and transcriptomic databases for potential impact of CDK8, CDK19, or their binding partner CCNC. sgRNA analysis of a panel of tumor cell lines showed that most tumor types represented in the panel, except for some central nervous system tumors, were not dependent on these genes. In contrast, analysis of clinical samples for alterations in these genes revealed a high frequency of gene amplification in two highly aggressive subtypes of prostate cancer and in some cancers of the GI tract, breast, bladder, and sarcomas. Analysis of survival correlations identified a group of cancers where CDK8 expression correlated with shorter survival (notably breast, prostate, cervical cancers, and esophageal adenocarcinoma). In some cancers (AML, melanoma, ovarian, and others), such correlations were limited to samples with a below-median tumor mutation burden. These results suggest that Mediator kinases are especially important in cancers that are driven primarily by transcriptional rather than mutational changes and warrant an investigation of their role in additional cancer types

Синтез бесфосфорных пиридинсодержащих глицеролипидов с простой эфирной связью.

The synthesis of new non-phosphorus ether glycerolipids containing a pyridinium ring in a polar domain is described. Novel compounds possess high cytotoxic activity against human leukemia К562 and colon cancer HCT116 cell lines.Описан синтез новых бесфосфорных глицеролипидов с простой эфирной связью, содержащих пиридиниевые основания в полярном домене. Показано, что данные соединения обладают высокой цитотоксической активностью для клеточных линий лейкоза человека К562 и рака толстой кишки НСТ116

Clinical Correlations of Polycomb Repressive Complex 2 in Different Tumor Types

PRC2 (Polycomb repressive complex 2) is an evolutionarily conserved protein complex required to maintain transcriptional repression. The core PRC2 complex includes EZH2, SUZ12, and EED proteins and methylates histone H3K27. PRC2 is known to contribute to carcinogenesis and several small molecule inhibitors targeting PRC2 have been developed. The present study aimed to identify the cancer types in which PRC2 targeting drugs could be beneficial. We queried genomic and transcriptomic (cBioPortal, KMplot) database portals of clinical tumor samples to evaluate clinical correlations of PRC2 subunit genes. EZH2, SUZ12, and EED gene amplification was most frequently found in prostate cancer, whereas lymphoid malignancies (DLBCL) frequently showed EZH2 mutations. In both cases, PRC2 alterations were associated with poor prognosis. Moreover, higher expression of PRC2 subunits was correlated with poor survival in renal and liver cancers as well as gliomas. Finally, we generated a Python application to analyze the correlation of EZH2/SUZ12/EED gene knockouts by CRISPR with the alterations detected in the cancer cell lines using DepMap data. As a result, we were able to identify mutations that correlated significantly with tumor cell sensitivity to PRC2 knockout, including SWI/SNF, COMPASS/COMPASS-like subunits and BCL2, warranting the investigation of these genes as potential markers of sensitivity to PRC2-targeting drugs