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Background: Chemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more effective and less toxic. Methods: MTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis. Results: We found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model. Conclusions: Our data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies. [ABSTRACT FROM AUTHOR]

4-(4-Bromopheny1)-2,3-dihydro- N,3-bis(3,4,5-trimethoxyphenyl)-2-oxoidmi-dazole-1-carboxamide (MZ3) is one of the novel synthesized Combretastatin A-4 analogs. In previous research, we found that MZ3 is a potent and specific compound against leukemia cell lines both in vitro and in vivo. In this paper, our purpose is to investigate the mechanisms of MZ3 induced cell cycle arrest and apoptosis in K562 cells. Cytotoxicity was measured by MTT method; apoptosis and cell cycle arrest were measured by flow cytometry. DNA fragmentation was tested by agarose gel electrophoresis. Protein expression was analyzed by western blotting. The polymerization of microtubules in cell was detected through immunofluorescence. MZ3 increases cyclin B1 levels and decreases the expression of cdc2, cdc25C and activation of Wee1. The changes in cdc2, cdc25C and Wee1 coincide with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. MZ3 induces apoptosis in K562 cells, proved by condensed DNA (DAPI stain) and DNA ladder. This apoptosis is related with the activation of caspase-9, caspase-3 and PARP cleavage, both of which are at the downstream of mitochondria. The changes of protein expression of Bcl-2 and Bax confirm the causal relationship between MZ3 and mitochondrial pathway, and the downregulation of AKT, p-AKT and XIAP indicate that the AKT pathway may participate in regulating this apoptosis. Moreover, MZ3 can reduce the soluble tubulin in K562 cells and inhibit microtubule assembly. MZ3 is a promising antileukemia compound with antimitotic and apoptotic activity that has potential for management of various leukemias. [ABSTRACT FROM AUTHOR]

4-(4-Bromophenyl)-2,3-dihydro- N,3-bis(3,4,5-trimethoxyphenyl)-2-oxoidmi-dazole-1-carboxamide (MZ3) is one of the synthesized combretastatin-A-4 analogues and has been reported that it displayed a promising specific activity against leukemia cell lines. Our purpose was to investigate the mechanism of MZ3’s cytotoxicity. Cytotoxicity was measured by MTT method, apoptosis was measured by flow cytometry. DNA fragmentation was tested by agarose gel electrophoresis. Mitochondrial membrane potential (ΔΨm) was detected by JC1 staining and flow cytometry, while intracellular reactive oxygen species (ROS) was detected by 5-(and-6)-carboxy-2′-7′-dichlorofluorescin diacetate staining and flow cytometry. Protein expression was analyzed by western blotting. In vivo activity of MZ3 was assayed through severe combined immunodeficiency (SCID) mice model of human leukemia engrafts. MZ3 exhibited high anti-cancer activity in six leukemia cell lines, including two drug-resistant cell lines. MZ3 induced DNA fragmentation, and caused an elevation of ROS and a loss of ΔΨm in HL60 cells. MZ3 also induced the activation of caspase-3, influenced the expression of Bcl-2 family members, MAPKs and other proteins relative to mitochondria-induced apoptosis. In addition, N-acetylcysteine cannot inhibit HL60 cell apoptosis caused by MZ3. Furthermore, a prolonged survival time was observed after treatment with MZ3 in SCID mice model of human leukemia engrafts. MZ3 is a potent compound against leukemia cell lines both in vitro and in vivo, and the mitochondrial pathway mediated by Bcl-2 protein family and MAPKs might be involved in signaling MZ3-induced apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Nickel, a metal commonly found in battery plants and welding factories, has potential cardiotoxicity, while all-trans retinoid acid (atRA) can promote cardiovascular repair and myocardial recovery. The purpose of this study was to investigate whether atRA could prevent cardiotoxicity induced by nickel both in vitro and in vivo. In the study, a rat myocardial cell line (H9c2) exposed to different concentrations of nickel chloride (NiCl2) displayed apoptotic features accompanied by reactive oxygen species generation. In addition, NiCl2 also caused obvious apoptosis and systolic dysfunction in primary myocardial cells. Treatment with atRA efficiently attenuated the cytotoxicities triggered by NiCl2 as it significantly mitigated ROS generation and decreased MAP kinases activity in NiCl2-treated cardiomyocytes. Additionally, NiCl2 exposure caused obvious arrhythmia in Sprague–Dawley rats with the maximum tolerance dose of NiCl2 between 2 and 3mg/kg. A combinational intragastric administration of 40mg/kg atRA can partially reverse NiCl2-induced arrhythmia in rats. Our results suggested that atRA might have therapeutic potential in alleviating the adverse effects of nickel on the cardiovascular system. [Copyright &y& Elsevier]

Abstract: A series of novel 2-aliphatic cyclic amine-3-(arylsulfonyl)quinoxalines was synthesized based on the structural features of a previously identified lead, WR1. The 2-piperidinol-3-(arylsulfonyl)quinoxalines, which showed excellent antitumor activities against five human cell lines, with inhibitory activities ranging from 0.34 to 2.32μM, proved to be a promising class of novel PI3Kα inhibitors. The most potent compound 10d (WR23) showed an inhibitory IC50 value of 0.025μM against PI3Kα and significant pAkt suppression effect. Molecular docking analysis was performed to determine possible binding modes between PI3Kα and target compounds. [Copyright &y& Elsevier]

Abstract: A series of cis-restricted 3,4-diaryl-5-aminoisoxazoles have been synthesized and evaluated for their biological activities. Among them, compound 11a and 13a displayed potent cytotoxic activities in vitro against five human cancer cell lines with IC50 values in the low micromolar range and two compounds inhibited tubulin polymerization with IC50 value of 1.8, and 2.1μM, respectively, similar to that of CA-4. Compound 13a could arrest at the G2/M phase of the cell cycle at the concentration of 0.1 and 1.0μM and induce apoptosis at 0.1–1.0μM. [Copyright &y& Elsevier]

Abstract: A series of novel 7-azaindazolyl-indolyl-maleimides were synthesized and evaluated for their antiproliferative activity in vitro against various human cancer cell lines and protein kinase C inhibitory activity. Compounds 8a–c, 8e and 14a were the most promising compounds against K562, A549, ECA-109, KB and SMMC-7721 cell lines in vitro. Compounds 9a–j showed moderate PKC inhibition. Further mechanism of action studies revealed that the antiproliferative activity of compound 8b in KB cells might involve the mitochondria-mediated apoptosis pathway. [Copyright &y& Elsevier]

Abstract: BZYX was designed as a dual-binding-site acetylcholinesterase (AChE) inhibitor and selected from series of indanone derivatives. The present study was designed to examine the cognition-enhanced, anti-cholinesterase, and neuroprotective effects of BZYX. In the passive avoidance performance and radial arm maze, BZYX showed a comparable effect to donepezil and rivastigmine on memory deficits in different stages induced by scopolamine, NaNO2 and ethanol, respectively. Ellman''s assay indicated BZYX exhibited high inhibition on AChE activity. IC50 values for BZYX: 0.058±0.022 μM; donepezil: 0.019±0.004 μM; rivastigmine: 3.81±2.81 μM; glantamine: 3.01±1.85 μM and huperzine A: 0.053±0.016 μM. BZYX also presented great neuroprotecive function from apoptosis induced by hydrogen peroxide(H2O2) in PC12 cells. MTT assay and Annexin V-FITC Apoptosis Detection showed the viability of PC12 cells remarkably decreased with 400 μM H2O2, while it significantly increased when the cells were pretreated with 0.1–1.0 μM BZYX. BZYX pretreatment remarkably reversed the loss of mitochondria membrane potential (ΔΨm), scavenged reactive oxygen species formation induced by H2O2 and resulted in up-regulation of procaspase3 and xIAP protein level and down-regulation of phosphorylated JNK protein, p53 protein level and cleavage of caspase 3. It is speculated that the mitochondrial pathway, mediated by Bcl-2 family and Mitogen-Activated Protein Kinases (MAPKs), might involved in the neuroprotection of BZYX. These results first demonstrated that BZYX had neuroprotective effects as well as cognition enhancement and acetylcholinesterase inhibition. It is hopeful that BZYX becomes a potential candidate for use in the intervention for neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: Three series of γ-carboline derivatives were designed and synthesized. All the compounds were tested for their cytotoxic activities in vitro against five human tumor cell lines (A549, SGC, HCT116, MCF-7, K562) and one multi-drug resistant subline (K562R). Most compounds showed moderate to potent cytotoxic activities against the tested cell lines. Sulfonate 11f exhibited more potent cytotoxic activities against almost all of the tested cells in comparison with the positive control, taxol, with IC50 values ranging from 0.15 to 4.5μM. The structure–activity relationships were discussed and a statistically reliable QSAR model (r 2 =0.936, q 2 =0.581) was established by the CoMFA analysis performed using the cytotoxic data against K562 cell line as a template. [Copyright &y& Elsevier]

Abstract: A new series of aryl substituted imidazol-2-one derivatives structurally related to combretastatin A-4 (CA-4) were synthesized and evaluated for their cytotoxic activities in vitro against various human cancer cell lines including MDR cell line. The cytotoxic effects of compounds 7b and 7i proved to be similar to or greater than that of docetaxel. The highly active compound 7b also exhibited excellent inhibitory activity on tumor growth in vivo. [Copyright &y& Elsevier]

Abstract: A series of 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives 1 have been synthesized and evaluated for their cytotoxic activity in vitro against human leukemia cell lines: Molt-4, K562, HL60, human liver cancer cell Hep-G2, human prostate cancer cell PC-3 in hypoxia. Most of the compounds showed more potent activity than TPZ. Compounds 1i and 1m displayed encouraging superior activity against Molt-4 and HL-60 cell lines. Three potential derivatives received the test of the activity in hypoxia and in normoxia against Molt-4 and HL-60 cell lines and showed obvious hypoxia selectivity. Further mechanism study revealed that the cytotoxic activities of compounds 1i and 1k in Molt-4 cells might be mediated by modulation of p53 protein expression and mitochondrial membrane potential (ΔΨ m). [Copyright &y& Elsevier]