Cytotoxicity of rhein, the active metabolite of sennoside laxatives, is reduced by multidrug resistance-associated protein 1

Anthranoid laxatives, belonging to the anthraquinones as do anthracyclines, possibly increase colorectal cancer risk. Anthracyclines interfere with topoisomerase II, intercalate DNA and are substrates for P-glycoprotein and multidrug resistance-associated protein 1. P-glycoprotein and multidrug resistance-associated protein 1 protect colonic epithelial cells against xenobiotics. The aim of this study was to analyse the interference of anthranoids with these natural defence mechanisms and the direct cytotoxicity of anthranoids in cancer cell lines expressing these mechanisms in varying combinations. A cytotoxicity profile of rhein, aloe emodin and danthron was established in related cell lines exhibiting different levels of topoisomerases, multidrug resistance-associated protein 1 and P-glycoprotein. Interaction of rhein with multidrug resistance-associated protein 1 was studied by carboxy fluorescein efflux and direct cytotoxicity by apoptosis induction. Rhein was less cytotoxic in the multidrug resistance-associated protein 1 overexpressing GLC4/ADR cell line compared to GLC4. Multidrug resistance-associated protein 1 inhibition with MK571 increased rhein cytotoxicity. Carboxy fluorescein efflux was blocked by rhein. No P-glycoprotein dependent rhein efflux was observed, nor was topoisomerase II responsible for reduced toxicity. Rhein induced apoptosis but did not intercalate DNA. Aloe emodin and danthron were no substrates for MDR mechanisms. Rhein is a substrate for multidrug resistance-associated protein 1 and induces apoptosis. It could therefore render the colonic epithelium sensitive to cytotoxic agents, apart from being toxic in itself

Characterization of colon cancer cells: a functional approach characterizing CD133 as a potential stem cell marker

<p>Abstract</p> <p>Background</p> <p>Isolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures.</p> <p>Methods</p> <p>We characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of potential stem cell markers CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts, mRNA expression of these markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated <it>in vivo</it>.</p> <p>Results</p> <p>All five putative stem cell markers showed distinct expression patterns in the tumours examined. Two patient-derived cell lines highly expressed CD133 (> 85% of positive cells) and three other cell lines had an expression level of about 50% whereas in long-term culture based models CD133 expression ranged only from 0 to 20%. In 8/14 cell lines, more than 80% of the cells were positive for CD24 and 11/14 were over 70% positive for CD44. 10/14 cell lines expressed CDCP1 on ≥ 83% of cells. CXCR4 expression was determined solely on 94 L and SW480.</p> <p>Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated surface markers and showed single cell fractions expressing up to three markers simultaneously.</p> <p>Statistical analysis revealed that the CXCR4 mRNA level correlates negatively with the protein expression of CD133, CD44, CD24 and CDCP1 in cell lines and xenografts.</p> <p>A lower differentiation grade of donor material correlated with a higher CDCP1 mRNA expression level in the respective tumour model.</p> <p><it>In vivo </it>growth behaviour studies of SW620 revealed significantly higher take rates and shorter doubling times in the tumour growth of CD133 positive subclones in comparison to the unsorted cell line or CD133 negative subclones.</p> <p>Conclusions</p> <p>Our data revealed correlations in the expression of surface markers CD44 and CD24 as well as CD44 and CDCP1 and strongly suggest that CD133 is a stem cell marker within our colon carcinoma panel. Further studies will elucidate its role as a potential therapeutic target.</p

Regionale Standards: Ausgabe 2019

Die "Regionalen Standards" gehen zurück auf die Initiative eines gemeinsamen Arbeitskreises, bestehend aus Vertretern des Statistischen Bundesamtes, der Arbeitsgemeinschaft Sozialwissenschaftlicher Institute e.V. (ASI) und des ADM Arbeitskreis Deutscher Markt- und Sozialforschungsinstitute e.V. Sie stellen ein Angebot für die Forschung in der Bundesrepublik Deutschland dar. Die "Regionalen Standards" beschreiben Gebietsabgrenzungen und Instrumente zur Typisierung von Regionen, wie sie in der Bundesrepublik Deutschland von der amtlichen Statistik und/oder der Markt- und Sozialforschung in gewisser Regelmäßigkeit eingesetzt werden. Zusätzlich werden Datensätze aus unterschiedlichen Quellen vorgestellt, die für die Regionalisierung von Bevölkerungsumfragen genutzt werden können und für die Forschung (teils jedoch mit Einschränkungen) zur Verfügung stehen

Systematic quantification of gene interactions by phenotypic array analysis

A phenotypic array method, developed for quantifying cell growth, was applied to the haploid and homozygous diploid yeast deletion strain sets. A growth index was developed to screen for non-additive interacting effects between gene deletion and induced perturbations. From a genome screen for hydroxyurea (HU) chemical-genetic interactions, 298 haploid deletion strains were selected for further analysis. The strength of interactions was quantified using a wide range of HU concentrations affecting reference strain growth. The selectivity of interaction was determined by comparison with drugs targeting other cellular processes. Bio-modules were defined as gene clusters with shared strength and selectivity of interaction profiles. The functions and connectivity of modules involved in processes such as DNA repair, protein secretion and metabolic control were inferred from their respective gene composition. The work provides an example of, and a general experimental framework for, quantitative analysis of gene interaction networks that buffer cell growth

Chronic Myeloid Leukemia Patients in Prolonged Remission following Interferon-alpha Monotherapy Have Distinct Cytokine and Oligoclonal Lymphocyte Profile

Peer reviewe

The Nevados de Payachata volcanic region (18°S/69°W, N. Chile)

Subduction-related volcanism in the Nevados de Payachata region of the Central Andes at 18°S comprises two temporally and geochemically distinct phases. An older period of magmatism is represented by glaciated stratocones and ignimbrite sheets of late Miocene age. The Pleistocene to Recent phase (≤0.3 Ma) includes the twin stratovolcanoes Volcan Pomerape and Volcan Parinacota (the Nevados de Payachata volcanic group) and two small centers to the west (i. e., Caquena and Vilacollo). Both stratovolcanoes consist of an older dome-and-flow series capped by an andesitic cone. The younger cone, i. e., V. Parinacota, suffered a postglacial cone collapse producing a widespread debris-avalanche deposit. Subsequently, the cone reformed during a brief, second volcanic episode. A number of small, relatively mafic, satellitic cinder cones and associated flows were produced during the most recent activity at V. Parinacota. At the older cone, i. e., V. Pomerape, an early dome sequence with an overlying isolated mafic spatter cone and the cone-forming andesitic-dacitic phase (mostly flows) have been recognized. The two Nevados de Payachata stratovolcanoes display continuous major- and trace-element trends from high-K 2 O basaltic andesites through rhyolites (53%–76% SiO 2 ) that are well defined and distinct from those of the older volcanic centers. Petrography, chemical composition, and eruptive styles at V. Parinacota differ between pre- and post-debris-avalanche lavas. Precollapse flows have abundant amphibole (at SiO 2 > 59 wt%) and lower Mg numbers than postcollapse lavas, which are generally less silicic and more restricted in composition. Compositional variations indicate that the magmas of the Nevados de Payachata volcanic group evolved through a combination of fractional crystallization, crustal assimilation, and intratrend magma mixing. Isotope compositions exhibit only minor variations. Pb-isotope ratios are relatively low ( 206 Pb/ 204 Pb = 17.95–18.20 and 208 Pb/ 204 Pb = 38.2–38.5); 87 Sr/ 86 Sr ratios range 0.70612–0.70707, 143 Nd/ 144 Nd ratios range 0.51238–0.51230, and γ 18 O SMOW values range from + 6.8% o to + 7.6% o SMOW. A comparison with other Central Volcanic Zone centers shows that the Nevados de Payachata magmas are unusually rich in Ba (up to 1800 ppm) and Sr (up to 1700 ppm) and thus represent an unusual chemical signature in the Andean arc. These chemical and isotope variations suggest a complex petrogenetic evolution involving at least three distinct components. Primary mantle-derived melts, which are similar to those generated by subduction processes throughout the Andean arc, are modified by deep crustal interactions to produce magmas that are parental to those erupted at the surface. These magmas subsequently evolve at shallower levels through assimilation-crystallization processes involving upper crust and intratrend magma mixing which in both cases were restricted to end members of low isotopic contrast.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47805/1/445_2005_Article_BF01073587.pd