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Three new dihydrobenzofuran neolignans, mappiodoinins A-C ( 1 - 3 ), together with nine known analogues ( 4  - 12 ) were isolated from the stems and leaves of Mappianthus iodoies . Their structures with the absolute configurations were elucidated by extensive spectroscopic methods. This is the first time to find dihydrobenzofuran neolignans from the genus Mappianthus. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW-480 in vitro . Neolignans 1 - 12 showed significant cytotoxic effects against various human cancer cell lines with IC 50 values ranging from 0.16 to 18.62 μM. [ABSTRACT FROM AUTHOR]

A series of novel 1,2,3-triazole-linked isosteviol derivatives were designed and synthesized via Huisgen-click reaction. Their cytotoxicities in vitro against HCT-116 and JEKO-1 cells were screened. The preliminary bioassays indicated that most of the title compounds exhibited noteworthy cytotoxic activities. Particularly, the compound 10b revealed the most potent inhibitory activities against HCT-116 cells with IC 50 value of 2.987 ± 0.098 μM, which was better than that (3.906 ± 0.261 μM) of positive control cisplatin. On the basis of these bioactivity data, hologram quantitative structure–activity relationship (HQSAR) was performed, and a statistically reliable model with good predictive power ( r 2 = 0.848, q 2 = 0.544 and R 2 pred = 0.982) was achieved. Additionally, the contribution maps derived from the optimal model explained the individual atomic contributions to the activity for each molecule. [ABSTRACT FROM AUTHOR]

DNA alkylators busulfan (B) and melphalan (M) act synergistically with gemcitabine (G) against lymphoma cells. To further improve the cytotoxicity, we combined them with the histone deacetylase inhibitor panobinostat (P) and proteasome inhibitor bortezomib (V). Lymphoma cell lines U937 and J45.01, and patient-derived cell samples were exposed to these drugs and the effects on cell proliferation and apoptosis were quantified. The combination BMGPV was found to exert strong synergistic cytotoxicity. Drug exposure to these cells activated the ATM pathway and modified histones at the epigenetic level. Cell death was triggered by the production of reactive oxygen species (ROS), permeabilization of the mitochondrial membrane, upregulation of proapoptotic factors, and activation of caspases. Downregulation of anti-apoptotic proteins c-MYC, MCL-1, and BCL-2 and inhibition of the prosurvival PI3K-AKT-mTOR pathway, culminated in apoptosis. The results of this study support a clinical trial using BMGPV as a possible pre-transplant conditioning regimen for relapsed/refractory lymphoma patients. [ABSTRACT FROM PUBLISHER]

Two rhodium(iii) complexes (Rh(OQ)3 (1) and Rh(BrQ)2(CH3OH)Cl (2), HOQ = 8-hydroxyquinoline, HBrQ = 5-bromo-8-hydroxyquinoline) of 8-hydroxylquinoline were synthesized and characterized. By MTT assay, the in vitro cytotoxicity of complexes 1 and 2, compared with HOQ, HBrQ and cisplatin, was evaluated towards a series of tumor cell lines as well as the normal liver cell line HL-7702. Complexes 1 and 2 showed higher cytotoxicity against the tested tumor cell lines than the corresponding ligands, among which T-24 was the most sensitive cell line for complexes 1 and 2 (IC50 = 13.42 μM for 1, 18.91 μM for 2). Compared with cisplatin, complex 1 exhibited higher cytotoxicity against T-24 cells but lower cytotoxicity against HL-7702(IC50 = 15.93 μM). Considering the better cytotoxicity of complex 1 than complex 2 against T-24 cells, the underlying anticancer molecular mechanisms were also investigated. DNA interaction studies revealed that complex 1 interacted with ct-DNA mainly via an intercalative binding mode. Further investigation of intracellular mechanisms revealed that complex 1 caused G2 phase cell cycle arrest and induced T-24 cell apoptosis in a dose-dependent mode. Targeting the mitochondrial pathway, the apoptotic mechanism in T-24 cells treated with 1 was studied by ROS detection, intracellular Ca2+ concentration measurements and caspase-9/3 activity assay, which suggested that complex 1 induced T-24 cell apoptosis by the disruption of mitochondrial-related mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Fifteen novel hybrids containing diterpene skeleton and nitric oxide (NO) donor were prepared from isosteviol. All the compounds were tested on preliminary cytotoxicity, and the results showed that six target compounds (8c, 10b, 14a, 14c, 18c, and 18d) exhibited anti-proliferation activity on HepG2 cells, with 8c (IC50 =4.24μM) and 18d (IC50 =2.75μM) superior to the positive control CDDO-Me (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-acid methyl ester, IC50 =4.99μM); eleven target compounds (8a–c, 9a–c, 10a–b, 14a, 14c, 18d) exhibited anti-proliferation activities on B16F10 cells at different levels, among them, seven compounds were more potent than comptothecin (IC50 =2.78μM) and CDDO-Me (IC50 =5.85μM), particularly, 10b (IC50 =0.02μM) presented the strongest effect, which was selected as a candidate for further study. [Copyright &y& Elsevier]

A new copper(II) complex ligated by the naturally occurring alkaloid matrine (MT), [Cu(MT+H)2(H2O)3](ClO4)4(1) was synthesized upon reacting matrine with Cu(ClO4)2·6H2O. Characterized of complex 1 with elemental analysis, IR spectroscopy, and single-crystal X-ray diffraction revealed the molecular structure to be a pentacoordinate copper(II) complex with two monodentate matrinium ions (MT+H) coordinatedviacarbonyl oxygen atoms and three aqua ligands. The positive charge of the cation [Cu(MT+H)2(H2O)3]4+is balanced by four ClO−4anions. Complex 1 is cytotoxic toward MCF-7, SGC-7901, and SK-OV-3 tumor cell lines. Supplemental materials are available for this article. Go to the publisher's online edition ofSynthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistryto view the supplemental file. [ABSTRACT FROM AUTHOR]

Abstract: Four mononuclear and iso-structural lanthanide complexes with 5,7-dibromo-8-quinolinol (H-BrQ): [Sm(BrQ)3(H2O)2]·0.5H2O (1), [Eu(BrQ)3(H2O)2]·1.33EtOH·0.33H2O (2), [Tb(BrQ)3(H2O)2]·0.5H2O (3), and [Dy(BrQ)3(H2O)2]·1.167EtOH·0.33H2O (4) were synthesized. Against BEL7404, SGC7901 and A549, complexes 1−4 exhibited enhanced cytotoxicity than H-BrQ or the corresponding lanthanide salts. The IC50 values of complexes 1, 3 against BEL7404 were 9.6 ± 2.2 and 10.1 ± 2.6 μM, while that of complex 4 against SGC7901 was 7.5 ± 2.1 μM. Complexes 1−4 against A549 yielded IC50 values in the range of 7.6 ± 1.5–29.6 ± 4.6 μM. The binding properties of H-BrQ and a model complex 1 to DNA were investigated by various methods. Results indicated that these lanthanide complexes interacted with DNA more strongly than free quinolinoline with intercalation being the most probable binding mode for both the complexes and quinolinoline. [Copyright &y& Elsevier]

A new E-ring γ-lactone pentacyclic triterpene, 3β-myristoxyurs-12-en-19,28-olide, has been isolated from the chloroform extract of Lysimachia clethroides Duby, together with four known pentacyclic triterpenoid acids. The structures of the compounds were elucidated by comprehensive spectroscopic analyses. All of the compounds showed various degrees of cytotoxic activities in MTT assay. [ABSTRACT FROM AUTHOR]

Aim:The efficacy of the Akt inhibitor perifosine against chronic myeloid leukemia (CML) cells and its mechanisms of action are unknown. In this study, the cytotoxic effects of perifosine on CML and acute myeloid leukemia (AML) cell lines were compared to elucidate the mechanisms underlying the differences.Methods:Human AML cell lines Kasumi-1 and HL-60, and the CML cell line K562 were used. Cell viability was quantitated using MTT assay. Apoptosis was determined using Annexin V-FITC/propidium iodide and Hoechst staining, which were followed by flow cytometry and fluorescence microscopy analysis, respectively. Caspase pathway activation and the expression of autophagy-related genes were examined using Western blot. Autophagy was studied using electron microscopy, the acridine orange staining method, and GFP-LC3 was examined with fluorescence microscopy.Results:In contrast to AML cell lines, the CML cell lines K562 and K562/G (an imatinib-insensitive CML cell line) were resistant to perifosine (2.5-20 μmol/L) in respect to inhibiting cell growth and inducing apoptosis. Perifosine (2.5, 5, and 10 μmol/L) inhibited Akt and its phosphorylation in AML cells, but not in CML cells. Treatment with perifosine (20 μmol/L) resulted in autophagy in CML cells as shown by the increased formation of acidic vesicular organelles and the accumulation of LC3-II. Treatment of CML cells with perifosine (5, 10, and 20 μmol/L) dose-dependently upregulated AGT5, but not Beclin 1 at the protein level. Furthermore, inhibition of autophagy by chloroquine (40 nmol/L) significantly suppressed the cell growth and induced apoptosis in CML cells treated with perifosine (20 μmol/L).Conclusion:Our results show that CML cell lines were resistant to the Akt inhibitor perifosine in vitro, which is due to perifosine-induced protective autophagy and upregulation of ATG5. [ABSTRACT FROM AUTHOR]

Liriodenine, an oxoaporphine alkaloid with anticancer activity isolated from Zanthoxylum nitidum (rutaceous anticancer traditional Chinese medicine), was selected as a bioactive ligand to react with HAuCl and NaAuCl to afford [LH][AuCl] ( 1) and [AuClL] ( 2), respectively (where L is liriodenine). The structures of 1 and 2 were characterized by IR spectroscopy, electrospray ionization mass spectrometry, H-NMR spectroscopy, and elemental analysis. The single-crystal X-ray diffraction analysis of 1 revealed that it is an ionic compound consisting of protonated liriodenine cation [LH] and [AuCl] anion. The spectroscopic analysis showed that 2 is a coordination compound, in which one liriodenine coordinates to gold via its 7-N donor. In aqueous solution, 1 is relatively stable, but 2 undergoes rapid hydrolysis. The in vitro cytotoxicity towards five human tumor cell lines shows that 1 and 2 manifest roughly similar biological behavior and appreciable antiproliferative properties, with IC values falling in the 2-16 μM range. The flow-cytometric analysis of 1 and 2 suggests that both compounds induced an S-phase arrest. Compounds 1 and 2 significantly poison topoisomerase I in vitro at low concentration (25 μM or less). DNA binding studies indicate that both 1 and 2 interact with DNA mainly via intercalation between the neighboring base pairs of the DNA double helix. Electrostatic interactions of 1 and 2 with the polyanionic DNA phosphate backbone may reinforce the intercalation because both 1 and 2 are composed of planar cationic species. Graphical abstract: Two liriodenine (L) gold(III) compounds [LH][AuCl] ( 1) and [AuClL] ( 2) were synthesized. The in vitro cytotoxicity towards five human tumor cell lines was tested and shows that 1 and 2 manifest appreciable antiproliferative properties, with IC values falling in the 2-16 μM range. Both 1 and 2 interact with DNA mainly via an intercalation mode, but electrostatic binding may exist. They both inhibit topoisomerase I activity at low concentration (25 μM or less). [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: Hydrogen sulfide (H2S) is a novel neurotransmitter. We studied here the effect of ACS 84, a new H2S releasing compound, on the cytotoxicity induced by amyloid beta (Aβ) in microglia. Treatment with Aβ1–40 (25μmol/L) for 24h significantly inhibited MTT reduction and increased lactate dehydrogenase release in BV-2 microglia cells. Pretreatment with ACS 84 (10μM) for 30min attenuated the above cytotoxicity caused by Aβ1–40, suggesting that ACS 84 may protect microglia against Aβ1–40-induced cell injury. ACS 84 also significantly attenuated nitric oxide release and TNF-α production in BV-2 cells treated with Aβ peptides (Aβ1–40 or Aβ1–42), but had no significant effect on the up-regulated protein expression of cyclooxygenase 2. These data suggest that ACS 84 may produce anti-inflammatory effect via inhibition of the release of inflammatory cytokines but not via suppression of the prostanoids production. Furthermore, pretreatment with ACS 84 also attenuated mitochondrial membrane potential loss (Δψ m) caused by Aβ1–40 in both microglia and neurons. To examine the underlying signaling mechanism, we detected the phosphorylation of p38-, JNK- and ERK-MAPKs. It was found that Aβ1–40 stimulated phosphorylation of all above three types of MAKPs. However, ACS 84 only attenuated the activation of p38 and JNK, but had no significant effect on that of ERK. Taken together, our data suggest that ACS 84 may protect Aβ-induced cell injury via anti-inflammation and preservation of mitochondrial function in a p38 and JNK dependent mechanism. Our work suggests that ACS 84 may have potential for the treatment of neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: Malignant melanoma is one of the most lethal and aggressive human malignancies. It is notoriously resistant to all of the current therapeutic modalities, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to the malignancy of melanoma. Dacarbazine (DTIC) has been considered as the gold standard for melanoma treatment with a response rate of 15–20%. Unfortunately, the resistance to this chemotherapeutic agent occurs frequently. ZD55-IL-24 is a selective conditionally replicating adenovirus that can mediate the expression of interleukin-24 (IL-24) gene, which has a strong anti-tumor effect. In this study, we hypothesized that a combination of ZD55-IL-24-mediated gene virotherapy and chemotherapy using DTIC would produce an increased cytotoxicity against human melanoma cells in comparison with these agents alone. Our results showed that the combination of ZD55-IL-24 and DTIC significantly enhanced the anti-tumor activity by more effectively inducing apoptosis in melanoma cells than either agent used alone without any overlapping toxicity against normal cells. This additive or synergistic effect of ZD55-IL-24 in combination with DTIC in killing human malignant melanoma cells implies a promising novel approach for melanoma therapy. [Copyright &y& Elsevier]

A series of novel isosteviol derivatives bearing amino alcohol and thiourea fragments have been stereo-selectively synthesized and screened for their in vitro cytotoxic activities against three human cancer cell lines (HCT-116, HGC-27 and JEKO-1). The results demonstrated that these compounds exhibited prominent cytotoxicities. Especially, the compound Iw displayed the most potent anticancer activities against HCT-116 cell with IC 50 value of 1.450 μM. On the basis of this bioassay results, these derivatives were further investigated by the hologram quantitative structure–activity relationship (HQSAR) technique. The optimal HQSAR model with q 2 = 0.663, r 2 = 0.895, SEE = 0.179 was generated using A/B/H/Ch as fragment distinction parameters and 4–7 as fragment size. This model was employed to predict the cytotoxic activities of test set compounds, and the predicted values were in good agreement with the experimental results. The contribution maps derived from the optimal model explained the individual atomic contribution to the total activity of single molecule. [ABSTRACT FROM AUTHOR]

Three cerium complexes: [Ce(ClQ)4] (1) (H-ClQ = 5,7-dichloro-8-hydroxylquinoline), [Ce(ClIQ)4]·CH2Cl2·0.5H2O (2) (H-ClIQ = 5-chloro-7-iodo-8-hydroxylquinoline) and [Ce2(BrQ)4(H-BrQ)(H2O)3Cl2]·1.5H2O (3) (H-BrQ = 5,7-dibromo-8-hydroxylquinoline) were synthesized. The structures of 1 and 2 are mononuclear whereas 3 has a binuclear structure. Compared with the H-ClQ, H-ClIQ and H-BrQ, complexes 1–3 exhibited significantly higher cytotoxicity (IC50 = 0.09–5.23 μM) to SK-OV-3 and BEL-7404, 1 and 2 exhibited higher cytotoxicity to NCI-H460. Most the complexes and ligands exhibited higher cytotoxicity than cisplatin. Complexes 1–3 are much more sensitive to SK-OV-3 than to human normal liver cell HL-7702. Their antitumor activities were achieved through cell apoptosis and arrest at G0/G1-phase. Studies on the binding properties of 1–3 to DNA indicate that intercalation is the most probable binding mode. [ABSTRACT FROM AUTHOR]

Abstract: New platinum(II) complexes containing aminophosphonate ester were synthesized and fully characterized, which were found to possess better solubility in both organic solvents and water than cisplatin. These platinum(II) complexes exhibited considerable cytotoxicity against tumor cells MG-63, SK-OV-3, HepG2, BEL-7404 and low cytotoxicity to normal human liver cells HL-7702. Their antitumor activities were achieved through the induction of cell apoptosis and the cell cycle arrest at G1 phase. The electrophoretic mobility studies and CD spectral analysis revealed that the binding mode of complex 6 to DNA might be different from that of cisplatin. [Copyright &y& Elsevier]

Abstract: Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone, H-PLN) was isolated from Plumbago zeylanica, the anticancer traditional Chinese medicine (TCM). Five new lanthanide(III) complexes of deprotonated plumbagin: [Y(PLN)3(H2O)2] (1), [La(PLN)3(H2O)2] (2), [Sm(PLN)3(H2O)2]⋅H2O (3), [Gd(PLN)3(H2O)2] (4), and [Dy(PLN)3(H2O)2] (5) were synthesized by the reaction of plumbagin with the corresponding lanthanide salts, in amounts equal to ligand/metal molar ratio of 3:1. The PLN–lanthanide(III) complexes were characterized by different physicochemical methods: elemental analyses, UV–visible, IR and 1H NMR and ESI-MS (electrospray ionization mass spectrum) as well as TGA (thermogravimetric analysis). The plumbagin and its lanthanide(III) complexes 1–5, were tested for their in vitro cytotoxicity against BEL7404 (liver cancer) cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The five PLN–lanthanide (III) complexes 1–5 effectively inhibited BEL7404 cell lines growth with IC50 values of 11.0±3.5, 5.1±1.3, 6.1±1.1, 6.4±1.3, and 9.8±1.5μM, respectively, and exhibited a significantly enhanced cytotoxicity compared to plumbagin and the corresponding lanthanide salts, suggesting a synergistic effect upon plumbagin coordination to the Ln(III) ion. The lanthanide complexes under investigation also exerted dose- and time-dependent cytotoxic activity. [La(PLN)3(H2O)2] (2) and plumbagin interact with calf thymus DNA (ct-DNA) mainly via intercalation mode, but for [La(PLN)3(H2O)2] (2), the electrostatic interaction should not be excluded; the binding affinity of [La(PLN)3(H2O)2] (2) to DNA is stronger than that of free plumbagin, which may correlate with the enhanced cytotoxicity of the PLN–lanthanide(III) complexes. [Copyright &y& Elsevier]

A charge-conversional and NIR responsive rapid release liposomal system (PSD/DOX/Cypate-BTSL) was developed to enhance therapeutic efficacy of cancer therapy. The cationic liposomes containing Cypate, doxorubicin (DOX) and NH 4 HCO 3 were shielded by pH-sensitive poly(methacryloyl sulfadimethoxine) (PSD) through electrostatic interaction at pH 7.4. At the tumor site (pH 6.5), PSD was deshielded and the liposomes displayed pH-sensitive charge reversal capability. The DOX released from PSD/DOX/Cypate-BTSL with irradiation was markedly higher than the other groups, indicating NIR irradiation and NH 4 HCO 3 had a significant effect on the drug release. After irradiation, the hyperthermia induced by Cypate could produce CO 2 bubbles quickly on account of the decomposition of NH 4 HCO 3 , achieving the rapid drug release. In 4T1 cells, PSD/DOX/Cypate-BTSL improved cellular uptake and cytotoxicity with irradiation at pH 6.5. In vivo results implied that the liposomes with irradiation could efficiently enhance the tumor accumulation and antitumor efficacy, and reduce systemic side effects of DOX. In conclusion, PSD/DOX/Cypate-BTSL is a promising candidate as a carrier for synergistic effects of PTT and chemotherapy. [ABSTRACT FROM AUTHOR]

Five new tigliane-type diterpenes (I)-(IV) are isolated along with four known phorbol ester analogues from the branches and leaves of Croton tiglium. [ABSTRACT FROM AUTHOR]

Two metal complexes of NiLCl 2 ( 1 ) and [PtLCl]Cl ( 2 ) with 4-([2,2′:6′,2″-terpyridin]-4′-yl)-N,N-diethylaniline ( L ) were synthesized and characterized. 1 and 2 exhibited selective cytotoxicity to T-24 cells more than L , compared with the normal liver cell line (HL-7702). Various experiments showed that L , 1 and 2 caused T-24 cell cycle arrest at S phase, as shown by the down-regulation of cdc25 A, cyclin A, cyclin B and CDK2 and the up-regulation of p21, p27 and p53. Furthermore, complexes 1 and 2 , especially complex 2 , acted as telomerase inhibitors targeting c-myc G-quadruplex DNA and triggered cell apoptosis. In addition, 1 and 2 also caused mitochondrial dysfunction. Taken together, we found that 1 and 2 exerted their cytotoxic activity mainly via inhibiting telomerase by interaction with c-myc quadruplex and disruption of mitochondrial function. [ABSTRACT FROM AUTHOR]

Three transition metal complexes with isoquinoline derivatives: [(MPDQ) 2 Zn(C 2 H 5 OH)ClO 4 ]ClO 4 ( 1 ) (MPDQ = 4,5-methylenedioxy-1-pyridinedihydroisoquinoline), [(PYP) 2 Zn(H 2 O)](ClO 4 ) 2 ( 2 ) (PYP = 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline) and [(MPDQ) 2 Ni(CH 3 OH)ClO 4 ]ClO 4 ( 3 ) were synthesized and fully characterized. All complexes exhibited strong proliferation inhibition activity against various tested cancer cells with high selectivity to tumour and normal cells. BEL-7404 cells were found most sensitive to complex 2 by inducing apoptosis. The process involved the mitochondrial membrane potential depolarization, PARP-proteins cleavage, Bcl-2, p53, p21 expression and caspase family members' activation. Taking these findings into account, it can propose that complex 2 induce cancer cell apoptosis via mitochondrial pathways. The interaction of complex 2 with DNA investigated by fluorescence, CD and viscosity indicated that complex 2 interact with DNA mainly via intercalation. [ABSTRACT FROM AUTHOR]

[Pt(Q) 2 ] ( 1 ) and [Pt(MQ) 2 ] ( 2 ) exhibited enhanced cytotoxicity against BEL-7404, Hep-G2, NCI–H460, T-24, A549 tumor cells but low cytotoxicity on normal HL-7702 cells. 1 and 2 could cause the cell cycle arrest in G2 and S phase, respectively. While pifithrin-α, a specific p53 inhibitor, induced cell cycle arrest in G1 phase. Although 1 , 2 and pifithrin-α caused serious inhibition on p53, 1 and 2 significantly cause the loss of mitochondrial membrane potential and increase of the reactive oxygen species level, cytochrome c , apaf-1 and caspase-3/9 ratio in BEL-7404 cells. 1 and 2 may trigger the cell apoptosis through a mitochondrial dysfunction pathway whereas pifithrin-α does not. The interactions of 1 and 2 with DNA are most probably via an intercalation. [ABSTRACT FROM AUTHOR]

A new platinum(II) complex of [Pt II (L) (pn)]Cl·2H 2 O ( 1 ) (pn = 1,3-propanediamine) with 2-(4-methoxy-phenyl)imidazo [4,5-f]-[1,10]phenanthrolin (H-L) was synthesized and characterized. In complex 1 , the platinum adopts a four-coordinated square planar geometry. Complex 1 exhibited selective cytotoxicity against NCI–H460, BEL-7402, SK-OV-3, SK-OV-3/DDP and HeLa cell lines with IC 50 values in the micromolar range (9.7–35.8 μM), but low cytotoxicity toward normal human liver HL-7702 cells. Complex 1 caused HeLa cell cycle arrest at S phase and it induced HeLa apoptosis by the activation of caspase-3/9. Various experiments showed that complex 1 preferred to bind with G-quadruplex in c-myc. Taken together, we found that complex 1 exerted its antitumor activity mainly via inhibiting telomerase by interaction with c-myc quadruplex and activation of caspase-3/9. [ABSTRACT FROM AUTHOR]

Abstract: Although it is well known that 3,4-methylenedioxymethamphetamine (MDMA) can cause various cardiovascular abnormalities and even sudden death from cardiac arrhythmia, whether it has any effect on myocardial gap junctions, which might be one of the targets mediating MDMA-induced cardiotoxicity, remains unclear. Objective: To test the hypothesis that MDMA may affect the myocardial gap junction protein connexin43 (Cx43) and induce cardiac dysrhythmia. Method: (1) In vivo study: adult rats were treated with a single dose MDMA administration (20mg/kg, i.p.). Electrocardiogram detection and immunohistochemical analysis were performed to evaluate cardiac function and expression of Cx43, respectively; (2) in vitro study: cultured ventricular myocytes of neonatal rats were treated with MDMA (10, 100, 1000μmol/L) for 1h. Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were performed to investigate the total Cx43 mRNA expression. Immunofluorescent analysis was used to evaluate the amount of junctional Cx43. The phosphorylation status of Cx43 at site Ser368 and intracellular Ca2+ oscillation were also studied. Results: Obvious changes in electrocardiographic patterns were found in rats following MDMA administration. They were characterized by prolonged QRS duration associated with increased amplitude of QRS complex. The heart rates in treated rats were significantly decreased compared to the rats in the control group. The immunohistochemical findings revealed a significant decrease in Cx43 expression. The in vitro study also showed a marked decline in total Cx43 protein associated with reduction of Cx43 mRNA, whereas the phosphorylated Cx43 at Ser368 was increased. Decrease of junctional Cx43 was found correlated with reduction in N-cadherin induced by high concentration of MDMA. Additionally, confocal microscopy findings revealed alteration of intracellular calcium oscillation patterns characterized by high frequency and increasing influx Ca2+. Conclusions: MDMA reduces expression of cardiac gap junction protein Cx43. The increase of phosphorylation status of Cx43 at Ser368 induced by MDMA is attributed, at least in part, to the Ca2+-dependent regulation of protein kinase C (PKC) activity. Our findings provide first evidence of MDMA-mediated changes in those cardiac gap junctions that may underlie MDMA-induced cardiac arrhythmia. [Copyright &y& Elsevier]

Abstract: Four isostructural lanthanide complexes with 5,7-dichloro-8-quinolinoline (H-ClQ): [Sm(ClQ)3(H2O)2]·1.33EtOH·0.33H2O (1), [Eu(ClQ)3(H2O)2]·0.5EtOH, (2), [Tb(ClQ)3(H2O)2]·0.5EtOH (3) and [Ho(ClQ)3(H2O)2]·H2O (4) were synthesized, in which the lanthanide was coordinated by three anions and two aqua ligands. The in vitro cytotoxicities of complexes 1−4 against five human tumor cells were evaluated. The IC50 values of complexes 1−4 against BEL7404, HeLa and A549 were in the range 1.2–6.3, 3.5–6.6 and 10.8–25.2 μM, respectively; except for complex 3 toward BEL7404, they all exhibited enhanced cytotoxicity in comparison to H-ClQ. The binding properties of complexes 1−4 to DNA examined by various methods indicated that complexes 1−4 interacted with DNA more strongly than free quinolinoline, and intercalation was the most probable binding mode for both the complexes and quinolinoline. [Copyright &y& Elsevier]

Abstract: A novel mannose-binding lectin (designated CML) was isolated from Clematis montana Buch.-Ham stem (Ranunculaceae) using ion exchange and gel filtration chromatographies on DEAE-Sepharose and Sephacryl S-100. The purified C. montana lectin was a homodimer of 11,968.9Da subunits as determined by gel filtration and MS. The hemagglutinating activity of CML was inhibited by branched oligomannosides. The N-terminal 15-amino acid sequence of CML, DNVKYSGQVKNTGSA, has not been reported for other lectins. Also, the peptide mass fingerprinting assay confirmed that there is no match result of similar plant lectins for CML, indicating CML may be a novel plant lectin. CML showed marked antiviral activity against various viruses in cell culture. Subsequently, CML was also found to exhibit remarkable inhibitory effect on L929, HeLa, MCF7 and HepG2 cells. Furthermore, CML specially induced L929 cell apoptosis in dose-dependent manner as evidenced by MTT, fluorescent microscopy, LDH activity-based cytotoxicity assays and DNA ladder. Moreover, due to both caspase inhibitors and Western blot analyses, caspase was also found to play the important role in the potential apoptotic mechanism of CML. When the carbohydrate-binding site was fully inhibited by sugars, cytotoxicity was abruptly decreased and apoptotic phenomenon in L929 cells was not observed, suggesting a significant correlation between mannose-binding-specific activity and the antineoplastic mechanism. [Copyright &y& Elsevier]

Abstract: A series of novel 6H-[1]benzothiopyrano[4,3-b]quinoline derivatives were prepared and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in human hepatoblastoma-derived liver Hep-G2 cells. Compounds 10g, 10h, 10j, 10l and 10o were found to be potent anti-HBV compounds with IC50 values less than 50μM. The most promising compound was 10l, with an IC50 value of 14.7μM and a SI value of 12.4. This is the first report of the anti-HBV effects of 6H-[1]benzothiopyrano[4,3-b] quinolin-9-ols. [Copyright &y& Elsevier]

Highlights • Busulfan plus cyclophosphamide (Bu+Cy) is an effective but toxic pretransplantation conditioning therapy. • Epigenetic modifiers enhance the efficacy of DNA alkylators. • Bu+Cy plus decitabine (Bu+Cy+DAC) is synergistically cytotoxic to acute myeloid leukemia (AML) cells regardless of P53 status. • FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)-positive AML cells are sensitized to Bu+Cy+DAC with sorafenib (Sor). • Bu+Cy+DAC±Sor may be used to personalize pretransplantation conditioning regimens. The combination of the DNA-alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pretransplantation conditioning therapy for myeloid leukemias. However, it is associated with significant nonrelapse mortality, which prohibits dose escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase antileukemic efficacy without jeopardizing patient safety. A preclinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC), and the hypomethylating agent decitabine (DAC) in human acute myeloid leukemia (AML) cell lines. Exposure of KBM3/Bu2506 (P53-null) and OCI-AML3 (P53-wild-type) cells to Bu+4HC inhibited cell proliferation by ∼35–39%; addition of DAC increased the inhibition to ∼60–62%. The observed synergistic interactions correlated with DNA damage response activation, increased the production of reactive oxygen species, and decreased mitochondrial membrane potential, release of mitochondrial proapoptotic proteins into the cytoplasm, and induction of caspase-dependent programmed cell death. The Bu+4HC+DAC combination further caused chromatin trapping of DNMT1 with a concomitant increase in DNA damage. In contrast, FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)-positive AML cell lines were not sensitized to Bu+4HC by inclusion of DAC; addition of the FLT3 kinase inhibitor sorafenib sensitized the FLT3-ITD-positive MV4-11 and MOLM13 cell lines to the triple drug combination by inhibiting the FLT3 signal transduction pathway. Our results therefore provide a rationale for the development of personalized conditioning therapy for patients with P53-mutated and FLT3-ITD-positive AML. [ABSTRACT FROM AUTHOR]

Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) combinations are efficacious in hematopoietic stem cell transplantation for myeloid leukemia. We sought to determine whether the more affordable drug cladribine (Clad) can provide a viable alternative to Clo, with or without panobinostat (Pano) and 5-aza-2′-deoxycytidine (DAC). Both Clad+Flu+Bu and Clo+Flu+Bu combinations showed synergistic cytotoxicity in KBM3/Bu250 6 , HL60, and OCI-AML3 cell lines. Cell exposure to these drug combinations resulted in 60%–80% inhibition of proliferation; activation of the ATM pathway; increase in histone modifications; decrease in HDAC3, HDAC4, HDAC5 and SirT7 proteins; decrease in mitochondrial membrane potential; activation of apoptosis and stress signaling pathways; and downregulation of the AKT pathway. These drug combinations activated DNA-damage response and apoptosis in primary cell samples from AML patients. At lower concentrations of Clad/Clo, Flu, and Bu, inclusion of Pano and DAC enhanced cell killing, increased histone modifications and DNA demethylation, and increased the levels of P16/INK4a, P15/INK4b and P21/Waf1/Cip1 proteins. The observed DNA demethylating activity of Clad and Clo may complement DAC activity; increase demethylation of the gene promoters for SFRP1 , DKK3 , and WIF1 ; and cause degradation of β-catenin in cells exposed to Clad/Clo+Flu+Bu+DAC+Pano. The overlapping activities of Clad/Clo+Flu+Bu, Pano, and DAC in DNA-damage formation and repair, histone modifications, DNA demethylation, and apoptosis may underlie their synergism. Our results provide a basis for supplanting Clo with Clad and for including epigenetic modifiers in the pre–hematopoietic stem cell transplantation conditioning regimen for myeloid leukemia patients. [ABSTRACT FROM AUTHOR]