Novel derivatives of spirohydantoin induce growth inhibition followed by apoptosis in leukemia cells

Hydantoin derivatives possess a variety of biochemical and pharmacological properties and consequently are used to treat many human diseases. However, there are only few studies focusing on their potential as cancer therapeutic agents. In the present study, we have examined anticancer properties of two novel spirohydantoin compounds, 8-(3,4-difluorobenzyl)-1′-(pent-4-enyl)-8-azaspiro[bicyclo[3.2.1] octane-3,4′-imidazolidine]-2′,5′-dione (DFH) and 8-(3,4-dichlorobenzyl)-1′-(pent-4-enyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′,5′-dione (DCH). Both the compounds exhibited dose- and time-dependent cytotoxic effect on human leukemic cell lines, K562, Reh, CEM and 8E5. Incorporation of tritiated thymidine ([³H] thymidine) in conjunction with cell cycle analysis suggested that DFH and DCH inhibited the growth of leukemic cells. Downregulation of PCNA and p-histone H3 further confirm that the growth inhibition could be at the level of DNA replication. Flow cytometric analysis indicated the accumulation of cells at subG1 phase suggesting induction of apoptosis, which was further confirmed and quantified both by fluorescence-activated cell sorting (FACS) and confocal microscopy following annexin V-FITC/propidium iodide (PI) staining. Mechanistically, our data support the induction of apoptosis by activation of the mitochondrial pathway. Results supporting such a model include, elevated levels of p53, and BAD, decreased level of BCL2, activation and cleavage of caspase 9, activation of procaspase 3, poly (ADP-ribosyl) polymerase (PARP) cleavage, downregulation of Ku70, Ku80 and DNA fragmentation. Based on these results we discuss the mechanism of apoptosis induced by DFH and its implications in leukemia therapy.     

接触抗癌药物的护士外周血淋巴细胞染色体畸变的观察

本文报道了职业性接触抗癌药的32名护士的外周血淋巴细胞染色体畸变的结果。结果表明接触组染色体畸变率明显高于对照组,与对照组比较差异有非常显著意义(P<0.01),且染色体畸变率与工龄呈平行关系。作者认为人体外周血淋巴细胞染色体畸变分析作为评价接触抗癌药对人体潜在危害的群体生物学监测指标是灵敏的。     

Garcinone E Blocks Autophagy Through Lysosomal Functional Destruction in Ovarian Cancer Cells

Background: High proliferative rate of cancer cells requires autophagy to maintain nutrient supply and intracellular homeostasis. As a result, impairing autophagic flux could be a novel strategy of cancer therapy. Aims and Objectives: In this study, the mechanism of a xanthone derivative isolated from Garcinia mangostana, garcinone E(GE), was investigated. Materials and Methods: Fluorescence assay was used to observe the accumulation and location of autophagosome and lysosome. Flow cytometry with Lyso-tracker red, MDC, and AO staining were applied to evaluate the lysosome accumulation and cellular acidity. Western blot and RT-qPCR were performed to evaluate the protein and mRNA levels, respectively. Results: GE could cause enhancement of LC3 II and p62 and the accumulation of autophagosome and lysosome. Meanwhile, it limited the protein level of Rab7, increased lysosomal pH, and inhibited the maturation of lysosomal hydrolases such as Cathepsin L, therefore blockaded the fusion of autophagosome and lysosome. Moreover, GE acted as a TFEB modulator by downregulating its protein level, which might contribute to autophagy dysfunction in ovarian cancer cells. Conclusions: GE interfered autophagosome–lysosome fusion in cancer cells, which demonstrated its application as an autophagy regulator and a potential therapeutic agent.     

The design and cytotoxic evaluation of some 1-aryl-3-isopropylamino-1-propanone hydrochlorides towards human Huh-7 hepatoma cells

A series of 1-aryl-3-isopropylamino-1-propanone hydrochlorides 1 and a related heterocyclic analog 2 as candidate antineoplastic agents were prepared and the rationale for designing these compounds is presented. A specific objective in this study is the discovery of novel compounds possessing growth-inhibiting properties of hepatoma cells. The compounds in series 1 and 2 were prepared and their structures established unequivocally. X-ray crystallography of two representative compounds 1d and 1g were achieved. Over half of the compounds are more potent than 5-fluorouracil which is an established drug used in treating liver cancers. QSAR evaluations and molecular modeling studies were undertaken with a view to detecting some physicochemical parameters which govern cytotoxic potencies. A number of guidelines for amplification of the project have been formulated.     

In-vitro antiproliferative activity of benzopyranone derivatives in comparison with standard chemotherapeutic drugs

The cytotoxic activities of five new benzopyranone derivatives containing basic amino side chain are described. Their cytotoxicities against ER(+) MCF‐7 and ER(–) MDA‐MB‐231 human breast cancer cell lines, and Ishikawa human endometrial cell line were determined after 72 h drug exposure employing CellTiter‐Glo assay at concentrations ranging from 0.01–1.0 × 10⁵ nM. The antiproliferative activities of these compounds were compared to tamoxifen (TAM), 4‐hydroxytamoxifen (4‐OHT, active metabolite of tamoxifen), and raloxifene (RAL). In‐vitro results indicated that compounds 9 , 10 , 12 , and 13 were more potent than TAM against the human breast cancer cell lines with IC₅₀ < 20 µM. The in‐silico structure–activity relationships of these compounds and their binding mode within the estrogen receptor (ER) binding site using AutoDock vina are discussed.     

Synthesis of novel thiazolyl-pyrimidines and their anticancer activity in vitro

A series of novel compounds 7-43 were prepared via the condensation of enaminones 4a-h and the guanidines carbonate 6a-f. The structures of these newly synthesized compounds were confirmed by (1) H-NMR, MS, EA and IR. All the compounds were tested for their cytotoxic activity in vitro against human cancer cell lines including Ishikawa, A549, BEL-7404, SPC-A-01 and SGC-7901. Most of them showed moderate cytotoxic against the tested cell lines. Among them, the most potent compounds 9 and 30 exhibited more efficient activity against Ishikawa, A549.     

Biomarkers of occupational exposure do anticancer agents: a minireview

The majority of anticancer agents has in common DNA-damaging properties and affects not only target-cells but also non-tumour cells. Its genotoxicity has been demonstrated in experimental models and in cancer patients treated with chemotherapy. Health care personnel involved in the preparation and administration of chemotherapy is therefore at risk for adverse health effects, since most environmental sampling studies demonstrated that there is widespread contamination of work surfaces and equipments with anticancer drugs. Adherence to safety guidelines and proper use of personal protective equipment are insufficient to prevent significant absorption, as evidenced by the presence of detectable amounts of drugs in urine samples and increased frequency of genotoxicity biomarkers. In this minireview, a critical appraisal of the most important biomarkers used for the evaluation of occupational exposure to anticancer agents as well as a summary of the key findings from several studies published in this field is performed.     

Bivalent sequential binding of docetaxel to methyl-β-cyclodextrin

New docetaxel (Dtx) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility (up to 9.98 mg mL⁻¹) were obtained from phase solubility diagrams. γ-CD and SBE-β-CD offered only poor solubility enhancements while considerable increases in apparent solubility were obtained with Me-β-CD (20%, w/w) and HP-β-CD (40%, w/w) (9.98 mg mL⁻¹ and 7.43 mg mL⁻¹, respectively). The complexation mechanism between Dtx and Me-β-CD was investigated by circular dichroism spectrometry, two-dimensional ¹H NMR (NOESY) in D₂O, isothermal titration calorimetry (ITC) and molecular docking calculations. Circular dichroism and NOESY confirmed the existence of non-covalent interactions between Dtx and Me-β-CD and suggested that the tert-butyl group (C₆-C₉) and two aromatic groups (C₂₄-C₂₉ and C₃₀-C₃₅) of Dtx interacted with the Me-β-CD molecules. The combination of ITC results to molecular docking calculations led to the identification of an unconventional sequential binding mechanism between Me-β-CD and Dtx. In this sequential binding, a Me-β-CD molecule first interacted with both tert-butyl and C₃₀-C₃₅ aromatic groups (K₁: 744 M⁻¹). Then a second Me-β-CD molecule interacted with the C₂₄-C₂₉ aromatic group (K₂: 202 M⁻¹). The entropy of the first interaction was positive, whereas a negative value of entropy was found for the second interaction. The opposite behavior observed for these two sites was explained by differences in the hydrophobic contact surface and functional group flexibility.     

抗肿瘤药物不良反应126例临床分析

目的分析抗肿瘤药物的不良反应发生情况,正确合理应用抗肿瘤药物,提高肿瘤患者生存率和生活质量,降低病死率、复发率及药物不良反应发生率。方法对2011年1月—12月我院126例患者使用抗肿瘤药物出现不良反应的情况进行统计分析。结果各系统不良反应发生率分别为消化系统63.4%,泌尿系统毒性12.7%,血液系统毒性15.9%,心脏毒性8.7%。有14.3%的患者需住院治疗并发症。结论抗肿瘤药物的临床应用,应根据个体差异,选用疗效相当、反应较轻的药物和不同的治疗手段,以达到理想的治疗效果。     

Synthesis and anticancer activity of Indolin-2-one derivatives bearing the 4-thiazolidinone moiety

A novel series of indolin‐2‐one derivatives containing the 4‐thiazolidinone moiety ( 5a—5p ) was synthesized and the cytotoxicity of these derivatives was evaluated in vitro against three human cancer cell lines (HT‐29, H460 and MDA‐MB‐231) by standard MTT assay. Some prepared compounds exhibited significant cytotoxicity against different human cancer cell lines. Several potent compounds were further evaluated against one normal cell line (WI‐38). In particular, the promising compound 5h showed remarkable cytotoxicity and selectivity against the HT‐29 and H460 cancer cell lines (IC₅₀ = 0.016 µmol/L, 0.0037 µmol/L, respectively).