1,721,130 research outputs found
Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774
No full textNew drugs and combination modalities for otherwise non-responsive brain tumors are urgently required. The anti-malarial artesunate (ART) and the EGFR tyrosine kinase inhibitor OSI-774 reveal profound cytotoxic activity. The effectiveness of a combination treatment and the underlying molecular determinants of cellular response are unknown. In the present investigation, we studied ART and OSI-774 in glioblastoma multiforme (GBM) cell lines. Supra-additive inhibition of cell growth was observed in U-87MG.DeltaEGFR cells transduced with a deletion-mutant constitutively active EGFR gene, while additive effects were present in cells transduced with wild-type EGFR (U-87MG.WT-2N), kinase-deficient EGFR (U-87MG.DK-2N), mock vector controls (U-87MG.LUX), or non-transduced parental U-87MG cells. Among nine other non-transduced GBM cell lines, supra-additive effects were found in two cell lines (G-210GM, G-599GM), while ART and OSI-774 acted in an additive manner in the other seven cell lines (G-211GM, G-750GM, G-1163GM, G-1187GM, G-1265GM, G-1301GM, and G-1408GM). Sub-additive or antagonistic effects were not observed. Genomic gains and losses of genetic material in the non-transduced cell lines as assessed by comparative genomic hybridization were correlated with the IC50 values for ART and OSI-774 and subsequently subjected to hierarchical cluster analysis and cluster image mapping. A genomic profile of imbalances was detected that predicted cellular response to ART and OSI-774. The genes located at the genomic imbalances of interest may serve as candidate resistance genes of GBM cells towards ART and OSI-774. In conclusion, the combination treatment of ART and OSI-774 resulted in an increased growth inhibition of GBM cell lines as compared to each drug alone. (C) 2004 Elsevier Inc. All rights reserved
CHEMICAL CHARACTERIZATION AND BIOACTIVITY OF AYURVEDIC CRUDE DRUGS AND RELATED PREPARATIONS: BOERHAAVIA DIFFUSA L., CONVOLVULUS PLURICAULIS CHOISY AND CURCULIGO ORCHIOIDES
No full textAyurveda, the traditional Indian medicine, is recognized by the European Union as non-conventional medicine and it includes more than 7000 plants used for therapeutic purposes in complex formulations poorly investigated under a chemical and biological point of view (Guerrini and Sacchetti, 2012). On these premises, preparations (decoction, DEC, and hydro-alcoholic extract, HE) of Boerhaavia diffusa L. (roots), Convolvulus pluricaulis Choisy (whole plant) and Curculigo orchioides Gaertn. (roots) were studied for the first time through a chemical and bioactivity approach. GC-FID, GC-MS, HPLC and HPTLC, and NMR strategies were employed to identify and quantify the main chemical compounds and to verify the repeatability of their fingerprinting. The study of biological activities was driven both by the ethnomedical traditional uses of the species in the Ayurvedic culture (Agrawal et al., 2011; Bhowmik et al., 2012; Chauhan et al., 2010) and by those aspects related to modern western phytotherapic culture: antioxidant activity; genotoxic and anti-genotoxic potential; and cytotoxicity against cancer and normal human cell lines. Ferulic acid and vanillin were identified and quantified in DEC and in HE of B. diffusa. However, HE showed the presence of other two characterising molecules: boeravinone B and eupalitin. β-sitosterol was identified and quantified in both preparations, but resulted more abundant in DEC. Ferulic acid showed antioxidant activity by ABTS assay higher than positive control. Preparations and pure compounds did not show anti-genotoxic activity towards two compounds with mutagenic properties. The study of cytotoxicity using DEC, HE and pure molecules against human cancer cell lines (A549, CaCo-2, MCF7, LoVo and HepG2), showed once more data far from those stated by the American National Cancer Institute (Suffness and Pezzuto, 1991). DEC of Convolvulus pluricaulis was characterised by the presence of phenolic acids (caftaric acid, caffeic acid, p-coumaric acid, iso-ferulic acid and tr-ferulic acid). Stigmasterol, β-sitosterol, lupeol and vanillin isomers and derivatives (2H4MB, 3H4MB and acetovanillone) were also detected in the same preparation. HE showed the presence of p-coumaric acid, vanillin, 2H4MB, acetovanillone, and vanillic acid, but the absence of phytosterols. The antioxidant activity evaluation indicated DEC as the preparation that exhibited always the best efficacy. HE showed instead an higher activity than DEC in the ABTS assay, no activity against DPPH radical and a lower capacity of blocking the radical propagation than DEC in the β-carotene bleaching test. Cytotoxic activity of the considered preparations against A549, CaCo-2, MCF7, LoVo and HepG2 cancer cell lines are not significant. The tests carried out with DEC and HE extracts against two leukaemia cell lines, drug-sensitive (CCRF-CEM) and multi-drug-resistant (CEM/ADR5000), showed, instead, interesting results: DEC CHCl3 extract and the HE soxhlet extract exhibit experimental data in line with the one stated by the American National Cancer Institute against the CCRF-CEM cell line, but respectively about 2 and 3 fold higher in the tests against CEM/ADR5000, showing cross-resistance phenomena. Curculigoside A and orcinol-β-D-glucoside were identified and quantified through HPLC methods in C. orchioides, and chosen as characterising compounds of preparations. β-sitosterol was also identified and quantified using GC-FID. The HE samples showed the highest antioxidant activity in every performed test. Regarding the anti-genotoxic activity, DEC resulted slightly more active than HE, but the highest activity was showed by orcinol-β-D-glucoside, even if it did not reach the 50% inhibition at the maximum concentration tested. The evaluation of the cytotoxic activity against human cancer cell lines exhibited an opposite trend, pointing out DEC as more active than HE for A549, CaCo-2, and HepG2. HE was instead more active against CCRF-CEM and CEM/ADR5000, but with IC50 data far from significant indication given by the American National Cancer Institute. Pure molecules did not exhibit any activity. However, further chemical and biological investigations will be carried out to shed an even more clear light on efficacy and safety of Ayurvedic preparations
Relationship between molecular variants and clinical manifestions in twelve glucose-6-phosphate dehydrogenase-deficient patients in Jordan
No full textUse of CpG island microarrays to identify colorectal tumors with a high degree of concurrent methylation
No full textWe provide a comprehensive description of our microarray-based technique for the simultaneous detection of multiple CpG islands in cancer. Amplicons from tumor and control samples were pools of differentially methylated CpG island fragments hybridized to a panel of similar to8000 CpG island tags. Data analysis identified 694 CpG island loci hypermethylated in a group of 14 colorectal tumors. The Stanford hierarchical cluster algorithm segregated the tumors into two subgroups, one of which exhibited a high level of concurrent hypermethylation while the other had little or no methylation, This is in agreement with previous observations of a CpG island methylation phenotype present in colorectal tumors. The present study demonstrates that this microarray-based technique is useful in classifying tumors according to their methylation profiles. (C) 2002 Published by Elsevier Science (USA).NCI NIH HHS [CA 69065, CA 84701
Daphne striata Tratt. and D. mezereum L.: a study of anti-proliferative activity towards human cancer cells and antioxidant properties
No full textIn this study, we investigated for the first time the anti-proliferative
and antioxidant properties of D. mezereum and D. striata. The aerial
parts were extracted by maceration with n-hexane, dichloromethane,
and methanol. MPLC, GC, and GC-MS were used for the phytochemical
study. The anti-proliferative activity was tested against MCF-7, A549,
LNCaP, ACHN, and C32 cancer human cells. The antioxidant activity was
measured by employing β-carotene bleaching, ABTS, DPPH, and FRAP
tests. The Relative Antioxidant Capacity Index (RACI) was applied from
the perspective of statistics. D. mezereum dichloromethane extract
showed a remarkable anti-proliferative with an IC50 of 6.08 μg/mL
against LNCaP cells. Experimental data indicate that Daphne species
have interesting anti-proliferative and antioxidant properties that
deserve more investigations to develop novel antineoplastic drugs
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines
No full textHomoharringtonine (HHT) is an ester of cephalotaxine (CET), both of which derive from the Chinese coniferous tree Cephalotaxus hainanensis. HHT inhibited tumor cell growth at molar ranges comparable to established cytostatic drugs, whereas CET was 3-4 orders of magnitude less active. Inhibition concentration 50% (IC50) values of CET and HHT were significantly correlated to doxorubicin, vincristine, methotrexate, cisplatin, or camptothecin in 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute (NCI, Bethesda, Md., USA). We tested both drugs for resistance of cell lines which selectively overexpress the multidrug resistance (MDR)-conferring genes P-glycoprotein/MDR1 (CEM/ ADR5000), MDR-related protein 1 MRP1 (HL60/AR), and breast cancer resistance protein BCRP (MDA-MB-231-BCRP). A threefold and ninefold resistance to HHT and CET, respectively, was found in CEM/ADR5000 cells, while the other MDR cell lines did not show cross-resistance compared to their drug-sensitive counterparts. As the tumor suppressor p53 is another important factor of chemoresistance, we also analyzed the possibility that p53 affects the response of tumor cells to CET and HHT. Comparing the p53 mutational status of the 55 NCI cell lines (http://dtp.nci.nih.gov) with the IC50 values showed a significant correlation. Thus, CET and HHT were more active in cell lines without p53 mutation. We correlated the IC50 values of CET and HHT with the cell doubling times of the 55 NCI cell lines as proliferation parameter and observed that rapidly growing cells were more susceptible than slowly growing cell lines. We conducted a search mining the NCI's database for the mRNA expression of 465 genes in 55 cell lines and correlated the data with the IC50 values for CET and HHT. Of these genes 61 (=13%) correlated with the IC50 values for CET and 122 (=26%) with the IC50 values for HHT indicating the multifactorial mode of action of these drugs in cancer cells. We have chosen one example from these genes to test a causative role for drug response. U-87MG.DeltaEGFR cells transfected with an epidermal growth factor receptor (EGFR) gene truncated in its extracellular domain through a deletion of exons 2-7 (DeltaEGFR) were 14-fold more resistant to HHT than control cells transfected with mock expression vector or non-transfected cells. The present investigation presents a starting point to dissect the genes and molecular pathways involved in the tumor cells' response to CET and HHT in greater detail.NCI NIH HHS [R01-CA77545
Daedalea gibbosa substances inhibit LPS-induced expression of iNOS by suppression of NF-kappaB and MAPK activities in RAW 264.7 macrophage cells.
No full textNitric oxide (NO) is a radical molecule produced by iNOS and plays a role in various physiological and pathophysiological conditions including inflammatory diseases and cancer. In the present study, organic extract of Daedalea gibbosa was effective in inhibiting NO and PGE2 production in RAW 264.7 cells. The extract of D. gibbosa was chemically fractionated leading to the isolation of three active fractions (F5-F7) that were effective in inhibiting NO and iNOS production. In addition, F6 and F7 significantly inhibited the iNOS transcript, while F5 did not cause a reduction in the iNOS transcript. Furthermore, the active fractions showed a differential effect on levels of phospho-p38, phospho-JNK, and phospho-IKBalpha. Phopsho-p38 was moderately inhibited by F5 and only F7 was significantly active in inhibiting phospho-IKBalpha. Interestingly, all active fractions significantly enhanced levels of phospho-JNK. In addition, the three active fractions also showed differential inhibitory effects on NF-kappaB DNA binding activity
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