Comparison of the interaction of doxorubicin, daunorubicin, idarubicin and idarubicinol with large unilamellar vesicles Circular dichroism study

AbstractDoxorubicin, daunorubicin and other anthracycline antibiotics constitute one of the most important groups of drugs used today in cancer chemotherapy. The details of the drug interactions with membranes are of particular importance in the understanding of their kinetics of passive diffusion through the membrane which is itself basic in the context of multidrug resistance (MDR) of cancer cells. Anthracyclines are amphiphilic molecules possessing dihydroxyanthraquinone ring system which is neutral under the physiological conditions. Their lipophilicity depends on the substituents. The amino sugar moiety bears the positive electrostatic charge localised at the protonated amino nitrogen. The four anthracyclines used in this study doxorubicin, daunorubicin, idarubicin and idarubicinol (an idarubicin metabolite readily formed inside the cells) have the same amino sugar moiety, daunosamine, with pKa of 8.4. Thus, all drugs studied will exhibit very similar electrostatic interactions with membranes, while the major differences in overall drug-membrane behaviour will result from their hydrophobic features. Circular dichroism (CD) spectroscopy was used to understand more precisely the conformational aspects of the drug–membrane systems. Large unilamellar vesicles (LUV) consisting of phosphatidylcholine, phosphatidic acid (PA) and cholesterol, were used. The anthracycline–LUV interactions depend on the molar ratio of phospholipids per drug. At low molar ratios drug:PA, these interactions depend also on the anthracycline lipophilicity. Thus, both doxorubicin and daunorubicin bind to membranes as monomers and their CD signal in the visible is positive. However, doxorubicin with its very low lipophilicity binds to the LUV through electrostatic interactions, with the dihydroxyanthraquinone moiety being in the aqueous phase, while daunorubicin, which is more lipophilic is unable to bind only through electrostatic interactions and actually the hydrophobic interactions are the only detected. The highly hydrophobic idarubicin, forms within the bilayer a rather complex entity involving 2–3 molecules of idarubicin associated in the right-handed conformation, one cholesterol molecule and also molecule(s) of phosphatidic acid, as this special oligomeric species is not detected in the absence of negatively-charged phospholipids. Idarubicinol differs from idarubicin with CH(13)–OH instead of C(13)O and its interactions with LUV are distinctly different. Its CD signal in the visible becomes negative and no self associations of the molecule within the bilayer could be detected. The variation of the sign of the Cotton effect (positive to negative) may derive from the changes in the C(6a)–C(7)–O(7)–C(1′) dihedral angle. It is noteworthy that C(13)–OH group, which strongly favours formation of the dimeric species in aqueous solutions when compared to idarubicin prevent association inside the LUV bilayer. At high ratios of phospholipids per drug all of them are embedded within the bilayer as monomer

Analysis of Multidrug Transporter in Living Cells. Inhibition of P-glycoprotein-mediated Efflux of Anthracyclines by Ionophores

One of the major obstacles of chemotherapy is that, after repeated treatments, cellular resistance to the drug appears. The problem is that the tumor cells become resistant not only to the drugs which have been used during the treatment but also to other drugs which are structurally and functionally unrelated. This is termed ‘multidrug resistance’ (MDR). MDR is frequently associated with decreased drug accumulation resulting from enhanced drug efflux. This is correlated with the presence of a membrane protein, P-glycoprotein, which pumps a wide variety of drugs out of cells thus reducing their toxicity. The search for molecules able to reverse MDR is very important. We here report that mobile ionophores such as valinomycin, nonactin, nigericin, monensin, calcimycin, lasalocid inhibit the efflux of anthracycline by P-glycoprotein whereas, channel-forming ionophores such as gramicidin do not. Cyclosporin which is also a strong Ca2+ chelating agent also inhibits the P-glycoprotein-mediated efflux of anthracycline

Degradation of Anthracycline Antitumor Compounds Catalysed by Metal Ions

The influence of some metal ions on the degradation of anthracyclines was examined. One of the degradation products is the 7,8-dehydro-9,10-desacetyldoxorubicinone, D* (¥), usually formed by hydrolysis at slightly basic pH. D* is a lipophilic compound with no cytostatic properties. Its formation could be responsible for the lack of antitumor activity of the parent compound. The coordination of metal ions to anthracycline derivatives is required to have degradation products. Cations such as Na+, K+, or Ca2+ do not induce the D* formation however metals which can form stable complexes with doxorubicin afford D*. Iron(III) and copper(II) form appreciable amount of D* at slightly acidic pH. Terbium(III) forms D* but its complex is stable only at slightly basic pH. Palladium(II) which does not form D*. The influence of the coordination mode of metal ions to anthracycline on the D* formation is discussed

A novel microarray approach reveals new tissue-specific signatures of known and predicted mammalian microRNAs

Microarrays to examine the global expression levels of microRNAs (miRNAs) in a systematic in-parallel manner have become important tools to help unravel the functions of miRNAs and to understand their roles in RNA-based regulation and their implications in human diseases. We have established a novel miRNA-specific microarray platform that enables the simultaneous expression analysis of both known and predicted miRNAs obtained from human or mouse origin. Chemically modified 2′-O-(2-methoxyethyl)-(MOE) oligoribonucleotide probes were arrayed onto Evanescent Resonance (ER) microchips by robotic spotting. Supplementing the complementary probes against miRNAs with carefully designed mismatch controls allowed for accurate sequence-specific determination of miRNA expression profiles obtained from a panel of mouse tissues. This revealed new expression signatures of known miRNAs as well as of novel miRNAs previously predicted using bioinformatic methods. Systematic confirmation of the array data with northern blotting and, in particular, real-time PCR suggests that the described microarray platform is a powerful tool to analyze miRNA expression patterns with rapid throughput and high fidelity

Recherches sur la formation, la composition et la structure de composés de coordination nitrés

I.’étude des systèmes [math], avec M = Zn, Cd, Hg, Mn, Ca, Sr, Ba, en solution aqueuse a permis de montrer la coexistence des composés [M(NO2)n](n-2)- avec 1 ≤ n ≤ 4. Dans les composés cristallisés [M(NO2)4]2-, les quatre ions [math] ont une disposition tétraédrique autour de l’ion M2+. La mesure des spectres d’absorption infrarouge et ultraviolet de ces composés, à l’état cristallisé et en solution aqueuse, a permis de mettre en évidence un mode de coordination particulier de l’ion [math] : les deux atomes d’oxygène sont reliés à l’ion métallique et la liaison métal-oxygène a un caractère fortement ionique

Recherches sur la formation, la composition et la structure de composés de coordination nitrés

L’application de la méthode de J. BJERRUM à l’étude des systèmes [math] d’une part, [math] d’autre part, en solution aqueuse, a permis de mettre en évidence la formation par étapes successives de cinq complexes nitro [Cu(NO2)n(H2O)6-n](n-2)- avec 1 ≤ n ≤ 5 dans le cas du cuivre et de trois complexes nitrito [Cr(ONO)n(H2O)6-n](n-3)- avec 1 ≤ n ≤ 3 dans le cas du chrome. Dans les deux cas, nous avons déterminé les constantes de formation et les spectres d’absorption des différents complexes.Dans le cas du système [math], en solution aqueuse, nous avons montré qu’il ne se formait qu’un seul complexe [Ni(NO2)2(H2O)2]

Activité optique des transitions de transfert de charge dans les complexes cis de cobalt (III) bis ethylènediamine

Dans le complexe cis de cobalt (III) bis éthylènediamine diaquo ( + ) [Co en2 (H2O),|Cl3 on prévoit et on observe quatre bandes de dicliroïsme circulaire correspondant au transfert de charge de l’éthylènediamine vers le cobalt. Les complexes cis [Co en2 X2]n+ avec X = NO2 -, Cl-, CN-, de configuration P (C2) présentent vers 220 nm une forte bande de dichroïsme circulaire négatif, que l’on attribue au transfert de charge X — Co. On retrouve cette forte bande négative dans les complexes cis [Co en2 XY]n+ de configuration supposée P(C2) avec d’une part X = NO2- et Y = Cl-, Br-, H2O et d’autre part X = Cl- et Y = Br-, H2O, NH3

Transport de différents substrats par la P-glycoprotéine (P-gp) et la MRP1. Rôle du glutathion

La résistance multiple aux antitumoraux qui peut apparaître lors de traitements anticancéreux est devenue un obstacle majeur à l'éfficacité de ces traitements. Fréquemment, le phénomène de résistance est associé à la surexpression de protéines membranaires telles que la P-glycoprotéine et la MRP1.The development of multidrug resistance is a major obstacle in the chemotherapeutic treatment of many human cancers. This phenomenon is generally associated to the overexpression of membrane proteins like P-glycoprotein or MRP1.PARIS13-BU Sciences (930792102) / SudocSudocFranceF