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ABSTRACT The aims of this study were to synthesize a series of thiosemicarbazones and their thiazole derivatives, to investigate their cytotoxic activity against three human cancers and normal (Vero cells) cell lines, and to evaluate the pro-apoptotic potential of the most active compounds. Materials and Methods: The thiosemicarbazones were obtained by reacting an aromatic aldehyde with thiosemicarbazide (yield 71-96%), which were subjected to a cyclization with α-bromoacetophenone to yield the required thiazole heterocycles (yield 63-100%). All the synthesized compounds were screened at 50 µM concentration against three cell lines representing HL60 (promyelocytic leukemia), Jurkat (acute lymphoblastic leukemia), and MCF-7 (breast cancer). The pro-apoptotic effect was measured by flow cytometry as the percentage of cells with hypodiploid DNA. Results: Three thiazole compounds showed activity against at least one tumor cell line (IC50 = 43-76 µM) and low cytotoxicity against Vero cells (IC50 > 100 M). The most active compound of this series induced 91% and 51% DNA fragmentation in HL60 and MCF-7 cell lines, respectively, suggesting that this compound triggered apoptosis in these cells. Conclusion: Among the synthesized compounds, one in particular was found to exert antiproliferative and pro-apoptotic activity on tumor cells and can be considered promising as a lead molecule for the design of new analogues with improved activity.
RESUMO O estudo teve como objetivo a síntese de uma série de tiossemicarbazonas e seus derivados tiazólicos e a avaliação da atividade citotóxica contra três linhagens de células tumorais humanas e células normais (Vero), a fim de se avaliar o potencial pró-apoptótico dos compostos mais ativos. As tiossemicarbazonas foram obtidas por reação entre um aldeído aromático e tiossemicarbazida (rend. 71-96%), as quais foram submetidas à ciclização com α-bromoacetofenona, fornecendo os heterociclos tiazólicos desejados (rend. 63-100%). Todos os compostos sintetizados foram testados na concentração de 50 µM contra três linhagens de células tumorais: HL60 (leucemia promielocítica), Jurkat (leucemia linfoblástica aguda) e MCF-7 (câncer de mama). O efeito pró-apoptótico foi avaliado por citometria de fluxo como porcentagem de células com DNA hipodiplóide. Três compostos tiazólicos foram ativos contra, pelo menos, uma linhagem tumoral (CI50=43-76 µM), com baixa citotoxicidade contra células Vero (CI50 > 100 M). O composto mais ativo dessa série induziu fragmentação do DNA de 91% e 51% nas linhagens HL60 e MCF-7, respectivamente, sugerindo que este composto ativou a apoptose nessas células. Dentre os compostos sintetizados, um em particular apresentou atividade antiproliferativa e pró-apoptótica em células tumorais e pode ser considerado composto protótipo promissor na busca por novos análogos com atividade melhorada.
Subject(s)
Thiazoles/chemistry , Thiosemicarbazones/toxicity , Vero Cells , Cell Line, TumorABSTRACT
Objective To study the effect of PPARγ ligand troglitazone (TGZ) on invasion and metastasis of gastric cancer cells, and investigate the relationship of PPARγ ligand with gastric cancer.Methods The expression of PPARγ in gastric cancer cell line MGC803 were detected by immunofluorescence cytochemistry method. The effect of different density TGZ on proliferation activity and adhesion of gastric cancer cell were detected by MTT chromatometry. The effect of different ligands on invasion and metastasis of gastric cancer cell MGC803 were detected by invasion system in vitro. Results The expression of PPARγ mainly located in cell nucleus. TGZ inhibited the proliferation of gastric cancer cell, decreased cell adhesion, locomotory capacity and invasion to matrigel, which had time and dose-dependent relationship.When treatment with 0. 1,1.0 and 10μ mol/ L TGZ, inhibition ratio of invasion and metastasis of cell was 8.79% ,31.31% ,51.42% and 28.29% ,4. 27% ,59. 27% respectively, which had statistical significance compared with control group( P <0. 05). When treatment was 10μ mol/L TGZ, cell adhesion was 0. 32 ±0. 03, it was statistically significant higher than that in control group (0. 52 ± 0. 04, P < 0. 05 ). Conclusion Human gastric cancer cell line MGC803 expressed functional PPARγ protein. TGZ inhibited adhesion and invasion of MGC803 cell on ECM at different degree, the effect of combination of two ligands was evident, which mechanism of action needed to be further investigated.
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Objective To systemically evaluate the therapeutic effect of pramipexole in treating Parkinson's disease. Methods Pubmed, Embase, Cochrane Database were used to search for randomized control trials (RCTs) on Parkinson's disease treated with pramipexole. Meticulous data wre extracted and meta-analysis was performed according to a preset protocol. Results Ten RCTs involving 1738 patients were included. The results of meta-analysis showed that pramipexole decreased the total scores of unified Parkinson's disease rating scale [UPDRS, WMD=-10.01,95%CI (-12.76,-7.26)],UPDRS part [WMD=-2.44,95%CI(-2.93,-1.95)],and UPDRS partⅢ[WMD=-6.61,95%CI(-8.38,-4.84)]. Pramipexole also reduced the score of UPDRS part Ⅳ[WMD=-0.73,95%CI(-1.16,-0.30)] in advanced patients(P＜0.05＝.Three studies referred to the effect of pramipexole in treating parkinsonian tremor. However there was a clinical heterogeneity among the studies, and two of them revealed a significant difference. Conclusions Pramipexole might improve motor symptoms and the quality of life in advanced patients, as well as improve tremor, which needs more RCTs to be confirmed.
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Objective To evaluate the roles of positron emission tomography (PET) with N-methyl [11C]2-(4' -methylaminophenyi-6-hydroxybenzathiazole) (11C-PIB) in the early diagnosis of Alzheimer's disease (AD).Methods Six AD patients,7 mild cognitive impairment (MCI) patients and 6 normal controls (NC) were diagnosed and assessed with brain PET with 11C-PIB.The emission images obtained at 5,25 and 45 min after 11C-PIB administration were analysed.Results Using visual analysis to summarize the characteristics of the imagings of each group: comparing to NC,the AD patients show high 11C -PIB up take,and low clearance rate of 11C-PIB at 45 min.The imagings of MCI group show heterogeneous,overlapping with AD and NC group.The statistical analysis shows: in AD group,the standard uptake value (SUV) ratio of parietal lobe,frontal lobe,temporal lobe,occipital lobe and hippocampal at 45 min was 1.91±0.21,2.09±0.41,1.92±0.35,1.66±0.41,1.55±0.28 respectively,and were higher than that of NC group (value being 1.48±0.53,1.57±0.64,1.36±0.53,1.27±0.40,1.17±0.33) with statistical significance,t=8.114,5.620,5.705,3.650 and 2.866,P=0.0001,0.0002,0.0002,0.0045 and 0.0170 respectively.In MCI group,the SUV ratio of parietal lobe,frontal lobe,temporal lobe,occipital lobe and hippocampal at 45 min was 1.48 ± 0.53,1.57 ± 0.64,1.36±0.53,1.27 ± 0.40,1.17±0.33 respectively,and were higher than that of NC group,but there was no statistical significance.Conclusion 11C-PIB PET imaging can differentiate AD patients from normal and anticipate the transformation of MCI patients.
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Objective To investigate the expression of peroxisome proliferators-activated receptor ? (PPAR?) in trophoblast and relation between PPAR? ligands and trophoblast invasion.Methods We examined the expression of PPAR? by immunohistochemistry,immunocytochemistry and real time quantitative PCR.We next examined,using the cytotrophoblast culture model,the biological role of PPAR? ligands in vitro.Results PPAR? was mainly localized in the nuclei of villous cytotrophoblast and extravillous cytotrophoblast of cell islands and cell columns.In villous tissue and cultured trophoblast from early first trimester,the level of expression of PPAR? mRNA and protein was 36.0?5.1,13.4?3.1 and 1.35?0.08,1.13?0.11;from late first trimester it was 23.3?5.5,6.1?1.3 and 1.17?0.03,0.86 ?0.05,and the expression of PPAR? was obviously decreased (P
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Objective To evaluate the effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome (PCOS) Methods Rosiglitazone was given 4 mg daily to 30 patients with PCOS for 12 weeks Before and after treatment, body mass index(BMI), plasma glucose, insulin, levels insulin resistance index (HOMA IR), blood lipid spectrum, leptin, neuropeptide Y, and sex hormone concentrations and ovulation rate were determined and compared Results After 12 weeks of treatment, basal insulin level decreased from (18?8) to (12?7) mIU/L ( P
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Objective To explore the molecular defects of insulin signalling in polycystic ovary and in vitro effects of troglitazone, one of the insulin sensitizers thiazolidinediones on polycystic ovary syndrome(PCOS) Method The metabolic and mitogenic effects of insulin and insulin like growth factor 1 (IGF 1) were examined in cultured human ovarian luteinizing granulosa cells from PCOS ( n = 11) and normally ovulatory (as control, n = 33) women with vehicle or troglitazone (1 ?g/ml) Results Basal rates were similar, but there were significant decreases in insulin stimulated glucose incorporation into glycogen in PCOS cells, a metabolic action of insulin However, IGF 1 response was found to be about twice greater in PCOS cells at all experimental concentrations with respect to thymidine incorporation compared to control cells, a mitogenic action Troglitazone increased 2 3 fold the insulin induced glycogen synthesis, but reduced the IGF 1 augmented responses of DNA synthesis in PCOS cells to within the range of control granulosa cells As compared with control, PCOS granulosa cells had higher insulin receptor substrate 1 (IRS 1) expression, but lower IRS 2 expression IRS 2 protein levels were increased and IRS 1 levels were reduced by troglitazone treatment, with a greater extent in the former Conclusions There is a selective defect in insulin actions in PCOS granulosa cells, suggesting ovarian insulin resistance and this metabolic phenotype is associated with an enhanced IGF 1 mitogenic potential Troglitazone could divergently alter signal protein expressions and thus insulin actions, as an ovarian insulin sensitizer and mitogen/steroidogenic inhibitor in PCOS