Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

Inhibitors of apoptosis proteins (IAPs) inhibit caspase activity, allowing various cancers to reduce programmed cell death (apoptosis) and resist drug treatment. The second mitochondrial-derived activator of caspases (SMAC) protein is an endogenous IAP antagonist, which can be considered as a potential anticancer therapy. Small-molecule SMAC mimetics based on the Ala-Val-Pro-Ile motif have been validated as potent IAP antagonists. In particular, most bivalent SMAC mimetics, which target both the baculovirus IAP repeat 2 (BIR2) and BIR3 domains in X-linked IAP (XIAP), antagonize IAPs better than the corresponding monovalent mimetics. Here we focus on strategies for designing bivalent small-molecule SMAC mimetics and progress in using them to antagonize IAPs. We also consider their clinical potential. Our discussion will hopefully help guide further study of these interesting mimetics.     

Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15

The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC₅₀ values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 μM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase-3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan-caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy.     

Role of A20 in cIAP-2 Protection against Tumor Necrosis Factor α (TNF-α)-Mediated Apoptosis in Endothelial Cells

Tumor necrosis factor α (TNF-α) influences endothelial cell viability by altering the regulatory molecules involved in induction or suppression of apoptosis. However, the underlying mechanisms are still not completely understood. In this study, we demonstrated that A20 (also known as TNFAIP3, tumor necrosis factor α-induced protein 3, and an anti-apoptotic protein) regulates the inhibitor of apoptosis protein-2 (cIAP-2) expression upon TNF-α induction in endothelial cells. Inhibition of A20 expression by its siRNA resulted in attenuating expression of TNF-α-induced cIAP-2, yet not cIAP-1 or XIAP. A20-induced cIAP-2 expression can be blocked by the inhibition of phosphatidyl inositol-3 kinase (PI3-K), but not nuclear factor (NF)-κB, while concomitantly increasing the number of endothelial apoptotic cells and caspase 3 activation. Moreover, TNF-α-mediated induction of apoptosis was enhanced by A20 inhibition, which could be rescued by cIAP-2. Taken together, these results identify A20 as a cytoprotective factor involved in cIAP-2 inhibitory pathway of TNF-α-induced apoptosis. This is consistent with the idea that endothelial cell viability is dependent on interactions between inducers and suppressors of apoptosis, susceptible to modulation by TNF-α.     

Radiation-Sensitising Effects of Antennapedia Proteins (ANTP)-SmacN7 on Tumour Cells

The objective of this study was to investigate the underlying mechanisms behind the radiation-sensitising effects of the antennapedia proteins (ANTP)-smacN7 fusion protein on tumour cells. ANTP-SmacN7 fusion proteins were synthesised, and the ability of this fusion protein to penetrate cells was observed. Effects of radiation on the expression of X-linked inhibitor of apoptosis protein (XIAP) were detected by western blotting. The radiation-sensitising effects of ANTP-SmacN7 fusion proteins were observed by a clonogenic assay. The effects of drugs and radiation on tumour cell apoptosis were determined using Annexin V/FITC double staining. Changes in caspase-8, caspase-9 and caspase-3 were detected by western blot before and after ANTP-SmacN7 inhibition of XIAP. The ANTP-SmacN7 fusion protein could enter and accumulate in cells; in vitro XIAP expression of radiation-induced tumour cells was negatively correlated with tumour radiosensitivity. The ANTP-SmacN7 fusion protein promoted tumour cell apoptosis through the activation of caspase3. ANTP-SmacN7 fusion protein may reduce tumour cell radioresistance by inducing caspase3 activation.     

姜黄素对HeLa细胞增殖和凋亡的影响

目的探讨姜黄素对HeLa细胞增殖和凋亡的影响及其机制。方法分别用10、20、40μmol/L姜黄素处理HeLa细胞24h后,MTT法检测细胞的增殖,光镜观察细胞形态,TUNEL技术检测细胞的凋亡,免疫细胞化学法检测Cytochrome C和Caspase-9蛋白的表达,Western blot法检测XIAP蛋白的表达。结果姜黄素对HeLa细胞的增殖有抑制作用,并呈剂量依赖性;部分细胞呈现典型的凋亡形态学改变;姜黄素作用后,Cytochrome C和Caspase-9蛋白的表达显著增强,XIAP蛋白的表达显著下降,且均呈剂量依赖性。结论姜黄素能抑制HeLa细胞增殖并诱导其凋亡,Cytochrome C和Caspase-9的表达上调及XIAP的表达下调可能参与凋亡过程。     

Antileukemic Natural Product Induced Both Apoptotic and Pyroptotic Programmed Cell Death and Differentiation Effect

Acute myeloid leukemia (AML) is one of the most common forms of leukemia. Despite advances in the management of such malignancies and the progress of novel therapies, unmet medical needs still exist in AML because of several factors, including poor response to chemotherapy and high relapse rates. Ardisianone, a plant-derived natural component with an alkyl benzoquinone structure, induced apoptosis in leukemic HL-60 cells. The determination of dozens of apoptosis-related proteins showed that ardisianone upregulated death receptors and downregulated the inhibitor of apoptosis protein (IAPs). Western blotting showed that ardisianone induced a dramatic increase in tumor necrosis factor receptor 2 (TNFR2) protein expression. Ardisianone also induced downstream signaling by activating caspase-8 and -3 and degradation in Bid, a caspase-8 substrate. Furthermore, ardisianone induced degradation in DNA fragmentation factor 45 kDa (DFF45), a subunit of inhibitors of caspase-activated DNase (ICAD). Q-VD-OPh (a broad-spectrum caspase inhibitor) significantly diminished ardisianone-induced apoptosis, confirming the involvement of caspase-dependent apoptosis. Moreover, ardisianone induced pyroptosis. Using transmission electron microscopic examination and Western blot analysis, key markers including gasdermin D, high mobility group box1 (HMGB1), and caspase-1 and -5 were detected. Notably, ardisianone induced the differentiation of the remaining survival cells, which were characterized by an increase in the expression of CD11b and CD68, two markers of macrophages and monocytes. Wright–Giemsa staining also showed the differentiation of cells into monocyte and macrophage morphology. In conclusion, the data suggested that ardisianone induced the apoptosis and pyroptosis of leukemic cells through downregulation of IAPs and activation of caspase pathways that caused gasdermin D cleavage and DNA double-stranded breaks and ultimately led to programmed cell death. Ardisianone also induced the differentiation of leukemic cells into monocyte-like and macrophage-like cells. The data suggested the potential of ardisianone for further antileukemic development.     

Optical Control of Antibody Activity by Using Photocleavable Bivalent Peptide–DNA Locks

Antibody-based molecular recognition plays a central role in today's life sciences, ranging from immunoassays to molecular imaging and antibody-based therapeutics. Control over antibody activity by using external triggers such as light could further increase the specificity of antibody-based targeting. Here we present bivalent peptide–DNA ligands containing photocleavable linkers as a noncovalent approach by which to allow photoactivation of antibody activity. Light-triggered cleavage of the 3-amino-3-(2-nitrophenyl)propionic acid peptide linker converted the high-affinity bivalent peptide–DNA lock into weakly binding monovalent ligands, effectively restoring antibody targeting of cell-surface receptors. In this work, a proof of principle was provided with an anti-hemagglutinin antibody, but the molecular design of the lock is generic and applicable to any monoclonal antibody for which an epitope or mimotope of sufficient affinity is available.     

Apoptotic Effects of Anthocyanins from Vitis coignetiae Pulliat Are Enhanced by Augmented Enhancer of the Rudimentary Homolog (ERH) in Human Gastric Carcinoma MKN28 Cells

Evidence suggests that augmented expression of a certain gene can influence the efficacy of targeted and conventional chemotherapies. Here, we tested whether the high expression of enhancer of the rudimentary homolog (ERH), which serves as a prognostic factor in some cancers, can influence the efficacy of anthocyanins isolated from fruits of Vitis coignetiae Pulliat, Meoru in Korea (AIMs) on human gastric cancer cells. The anticancer efficacy of AIMs was augmented in ERH-transfected MKN28 cells (E-MKN28 cells). Molecularly, ERH augmented AIM-induced caspase-dependent apoptosis by activating caspase-3 and -9. The ERH-augmented apoptotic effect was related to mitochondrial depolarization and inhibition of antiapoptotic proteins, XIAP, and Bcl-2. In addition, reactive oxygen species (ROS) generation was augmented in AIMs-treated E-MKN28 cells compared to AIMs-treated naïve MKN28 cells. In conclusion, ERH augmented AIM-induced caspase-dependent mitochondrial-related apoptosis in MKN28 cells. A decrease in expression of Bcl-2 and subsequent excessive ROS generation would be the mechanism for ERH-augmented mitochondrial-related apoptosis in AIMs-treated MKN28 cells. A decrease in expression of XIAP would be another mechanism for ERH-augmented caspase-dependent apoptosis in AIMs-treated MKN28 cells.     

The Caspase Pathway of Linoelaidic Acid (9t, 12t-C18:2)-Induced Apoptosis in Human Umbilical Vein Endothelial Cells

Trans fatty acids (TFA) are reported to contribute to inflammation and coronary heart disease. The study aim was to investigate the proapoptotic effects of two double bond TFA (TDTFA) on human umbilical vein endothelial cells (HUVEC). The HUVEC were grown in media supplied with linoelaidic acid (9t,12t-C18:2) at 50, 100, 200, 400 μmol/l for 24 or 48 h to examine the effects of TDTFA on the viability and apoptosis of these cells. Flow cytometry analysis and confocal scanning were used to measure apoptosis, cell binding of Annexin V and propidium iodide uptake. Colorimetric assay and RT-PCR were used to analyze enzyme activities and mRNA expression of caspase-3, -8 and -9 in HUVEC. Results showed that 9t,12t-C18:2 inhibited the viability of HUVEC in a dose-dependent and time-dependent manner. The percentages of 9t,12t-C18:2 induced apoptotic and necrotic cells significantly increased compared with that of the control. The activities and mRNA expression of caspase-8, -9 and -3 were significantly increased in 9t,12t-C18:2 treated cells compared to that of the control. Addition of specific inhibitors of caspase-8 (z-IETD-fmk) and caspase-9 (z-LEHD-fmk) to HUVEC was found to completely inhibit 9t,12t-C18:2-induced activation of caspase-3, and z-IETD-fmk inhibited the activation of caspase-9. Meanwhile, it was found that mRNA expression of Bid, Smac/DIABLO and the release of mitochondrial cytochrome c were significantly elevated by 9t,12t-C18:2 treatment. These results suggest that 9t,12t-C18:2 may induce apoptosis of HUVEC through activating caspase-8, -9 and -3. Both the death receptor pathway and the mitochondrial pathway may be involved in the apoptosis induced by 9t,12t-C18:2.     

Beta-hairpin peptidomimetics: design, structures and biological activities

The folded 3D structures of peptides and proteins provide excellent starting points for the design of synthetic molecules that mimic key epitopes (or surface patches) involved in protein-protein and protein-nucleic acid interactions. Protein epitope mimetics (PEMs) may recapitulate not only the structural and conformational properties of the target epitope but also their biological activities. By transferring the epitope from a recombinant to a synthetic scaffold that can be produced by parallel combinatorial methods, it is possible to optimize properties through iterative cycles of library synthesis and screening, and even to evolve new biological activities. One very interesting scaffold is found in beta-hairpin motifs, which are used by many proteins to mediate molecular recognition events. This motif is readily amenable to PEM design, for example, by transplanting hairpin loop sequences from folded proteins onto hairpin-stabilizing templates, such as the dipeptide D-Pro-L-Pro. In addition, beta-hairpin peptidomimetics can also be exploited to mimic other types of epitopes, such as those based on alpha-helical secondary structures. The size and shape of beta-hairpin PEMs appear well suited for the design of inhibitors of both protein-protein and protein-nucleic acid interactions, endeavors that have so far proven difficult using small "drug-like" molecules. In recent work, it was shown that beta-hairpin PEMs can be designed that mimic the canonical conformations of antibody hypervariable loops, suggesting that novel small-molecule antibody mimics may be feasible. Using naturally occurring peptides as starting points, beta-hairpin mimetics have been discovered that possess antimicrobial activity, while others are potent inhibitors of the chemokine receptor CXCR4. Beta-hairpin PEMs have also been designed and optimized that mimic an alpha-helical epitope in p53 and so block its interaction with HDM2. A crystal structure of one HDM2-mimetic complex revealed how the surface of the protein had adapted to the shape of the hairpin, thereby enhancing inhibitor affinity. Small folded RNA motifs also make interesting targets for inhibitor design. For example, beta-hairpin mimetics have been designed and optimized that bind with high affinity and good selectivity to the TAR and RRE RNA motifs from HIV-1. Solution structures of the mimetics both free and bound to the RNA target provided some surprises, as well as an improved understanding of the mechanisms of binding. These mimetics represent still a relatively new family of RNA-binding molecules, but clearly one with potential for development into novel antiviral agents.     

DNA-Nanoscaffold-Assisted Selection of Femtomolar Bivalent Human α-Thrombin Aptamers with Potent Anticoagulant Activity

Multivalent aptamers that interact with their target proteins through multiple sites exhibit much stronger binding strengths than their monovalent counterparts. In this work, we have designed a single-stranded DNA (ssDNA) library (10¹⁵ molecules, each 145 nt) based on a predefined DNA nanostructure designed to present two random-loop sites for bivalent aptamer evolution. From this library, a group of ultra-strong bivalent aptamers against human α-thrombin (with apparent K_D values of ≈340 fm ) were easily identified through a simple seven-round conventional systematic evolution of ligands by exponential enrichment (SELEX) procedure. The dominant bivalent aptamers consist of two components, one binding to exosite I and the other to exosite II. The best of these bivalent aptamers show strong allosteric attenuation of the thrombin cleavage activity and also display an extremely potent anticoagulation effect in human plasma, demonstrating their great potential in therapeutic applications. The method developed here can easily be adapted to conventional SELEX techniques, opening a new route for fast selection of multivalent aptamers with superior binding affinity for other targets.     

Bifunctional ligands that target cells displaying the alpha v beta3 integrin

Strategies to eliminate tumor cells have long been sought. We envisioned that a small molecule could be used to decorate the offending cells with immunogenic carbohydrates and evoke an immune response. To this end, we describe the synthesis of bifunctional ligands possessing two functional motifs: one binds a cell-surface protein and the other binds a naturally occurring human antibody. Our conjugates combine an RGD-based peptidomimetic, to target cells displaying the alpha v beta3 integrin, with the carbohydrate antigen galactosyl-alpha(1-3)galactose [Galalpha(1-3)Gal or alpha-Gal]. To generate such bifunctional ligands, we designed and synthesized RGD mimetics 1 b and 2 c, which possess a free amino group for modification. These compounds were used to generate bifunctional derivatives 1 c and 2 d, with dimethyl squarate serving as the linchpin; thus, our synthetic approach is modular. To evaluate the binding of our peptidomimetics to the target alpha v beta3-displaying cells, we implemented a cell-adhesion assay. Results from this assay indicate that the designed, small-molecule ligands inhibit alpha v beta3-dependent cell adhesion. Additionally, our most effective bifunctional ligand exhibits a high degree of selectivity (4000-fold) for alpha v beta3 over the related alpha v beta5 integrin, a result that augurs its utility in specific cell targeting. Finally, we demonstrate that the bifunctional ligands can bind to alpha v beta3-positive cells and recruit human anti-Gal antibodies. These results indicate that both the integrin-binding and the anti-Gal-binding moieties can act simultaneously. Bifunctional conjugates of this type can facilitate the development of new methods for targeting cancer cells by exploiting endogenous antibodies. We anticipate that our modifiable alpha v beta3-binding ligands will be valuable in a variety of applications, including drug delivery and tumor targeting.     

Stability and Cell Permeability of Sulfonyl Fluorides in the Design of Lys-Covalent Antagonists of Protein-Protein Interactions

Recently we reported on aryl-fluorosulfates as possible stable and effective electrophiles for the design of lysine covalent, cell permeable antagonists of protein–protein interactions (PPIs). Here we revisit the use of aryl-sulfonyl fluorides as Lys-targeting moieties, incorporating these electrophiles in XIAP (X-linked inhibitor of apoptosis protein) targeting agents. We evaluated stability in buffer and reactivity with Lys311 of XIAP of various aryl-sulfonyl fluorides using biochemical and biophysical approaches, including displacement assays, mass spectrometry, SDS gel electrophoresis, and denaturation thermal shift measurements. To assess whether these modified electrophilic “warheads” can also react with Tyr, we repeated these evaluations with a Lys311Tyr XIAP mutant. Using a direct cellular assay, we could demonstrate that selected agents are cell permeable and interact covalently with their intended target in cell. These results suggest that certain substituted aryl-sulfonyl fluorides can be useful Lys- or Tyr-targeting electrophiles for the design of covalent pharmacological tools or even future therapeutics targeting protein–protein interactions.     

A Bivalent Supramolecular GCP Ligand Enables Blocking of the Taspase1/Importin α Interaction

Taspase1 is a unique protease not only pivotal for embryonic development but also implicated in leukemia as well as solid tumors. As such, it is a promising target in cancer therapy, although only a limited number of Taspase1 inhibitors lacking general applicability are currently available. Here we present a bivalent guanidiniocarbonyl-pyrrole (GCP)-containing supramolecular ligand that is capable of disrupting the essential interaction between Taspase1 and its cognate import receptor Importin α in a concentration-dependent manner in vitro with an IC₅₀ of 35 μM. Here, size of the bivalent vs the monovalent construct as well as its derivation with an aromatic cbz-group arose as critical determinants for efficient interference of 2GC . This was also evident when we investigated the effects in different tumor cell lines, resulting in comparable EC₅₀ values (∼40–70 μM). Of note, in higher concentrations, 2GC also interfered with Taspase1’s proteolytic activity. We thus believe to set the stage for a novel class of Taspase1 inhibitors targeting a pivotal protein-protein interaction prerequisite for its cancer-associated proteolytic function.     

Bisdemethoxycurcumin Induces Cell Apoptosis and Inhibits Human Brain Glioblastoma GBM 8401/Luc2 Cell Xenograft Tumor in Subcutaneous Nude Mice In Vivo

Bisdemethoxycurcumin (BDMC) has biological activities, including anticancer effects in vitro; however, its anticancer effects in human glioblastoma (GBM) cells have not been examined yet. This study aimed to evaluate the tumor inhibitory effect and molecular mechanism of BDMC on human GBM 8401/luc2 cells in vitro and in vivo. In vitro studies have shown that BDMC significantly reduced cell viability and induced cell apoptosis in GBM 8401/luc2 cells. Furthermore, BDMC induced apoptosis via inhibited Bcl-2 (anti-apoptotic protein) and increased Bax (pro-apoptotic proteins) and cytochrome c release in GBM 8401/luc2 cells in vitro. Then, twelve BALB/c-nude mice were xenografted with human glioblastoma GBM 8401/luc2 cancer cells subcutaneously, and the xenograft nude mice were treated without and with BDMC (30 and 60 mg/kg of BDMC treatment) every 3 days. GBM 8401/luc2 cell xenografts experiment showed that the growth of the tumors was significantly suppressed by BDMC administration at both doses based on the reduction of tumor size and weights. BDMC did not change the body weight and the H&E histopathology analysis of liver samples, indicating that BDMC did not induce systemic toxicity. Meanwhile, treatment with BDMC up-regulated the expressions of BAX and cleaved caspase-3, while it down-regulated the protein expressions of Bcl-2 and XIAP in the tumor tissues compared with the control group. This study has demonstrated that BDMC presents potent anticancer activity on the human glioblastoma GBM 8401/luc2 cell xenograft model by inducing apoptosis and inhibiting tumor cell proliferation and shows the potential for further development to the anti-GBM cancer drug.     

The Anti-Proliferative and Apoptotic Effects of Rutaecarpine on Human Esophageal Squamous Cell Carcinoma Cell Line CE81T/VGH In Vitro and In Vivo

The overall five-year survival rate for patients with esophageal cancer is low (15 to 25%) because of the poor prognosis at earlier stages. Rutaecarpine (RTP) is a bioalkaloid found in the traditional Chinese herb Evodia rutaecarpa and has been shown to exhibit anti-proliferative effect on tumor cells. However, the mechanisms by which RTP confer these effects and its importance in esophageal squamous cell carcinoma treatment remain unclear. Thus, in the present study, we first incubated human esophageal squamous cell carcinoma cell line, CE81T/VGH, with RTP to evaluate RTP’s effects on tumor cell growth and apoptosis. We also performed a xenograft study to confirm the in vitro findings. Furthermore, we determined the expression of p53, Bax, bcl-2, caspase-3, caspase-9, and PCNA in CE81T/VGH cells or the tumor tissues to investigate the possible mechanisms. All the effects of TRP were compared with that of cisplatin. The results showed that RTP significantly inhibits CE81T/VGH cell growth, promotes arrest of cells in the G₂/M phase, and induces apoptosis. Consistently, the in vivo study showed that tumor size, tumor weight, and proliferating cell nuclear antigen protein expression in tumor tissue are significantly reduced in the high-dose RTP treatment group. Furthermore, the in vitro and in vivo studies showed that RTP increases the expression of p53 and Bax proteins, while inhibiting the expression of Bcl-2 in cancer cells. In addition, RTP significantly increases the expression of cleaved caspase-9 and cleaved caspase-3 proteins in tumor tissues in mice. These results suggest that RTP may trigger the apoptosis and inhibit growth in CE81T/VGH cells by the mechanisms associated with the regulation of the expression of p53, Bax, Bcl-2, as well as caspase-9 and caspase-3.     

Effects of Corchorusoside C on NF-κB and PARP-1 Molecular Targets and Toxicity Profile in Zebrafish

The present study aims to continue the study of corchorusoside C (1), a cardenolide isolated from Streptocaulon juventas, as a potential anticancer agent. A mechanistic study was pursued in a zebrafish model and in DU-145 prostate cancer cells to investigate the selectivity of 1 towards NF-κB and PARP-1 pathway elements. Compound 1 was found to inhibit the expression of IKKα and NF-κB p65 in TNF-α induced zebrafish and inhibit the expression of NIK in vitro. The protein expression levels of XRCC-1 were increased and p53 decreased in DU-145 cells. XIAP protein expression was initially decreased after treatment with 1, followed by an increase in expression at doses higher than the IC₅₀ value. The activity of caspase-1 and the protein expression levels of IL-18 were both decreased following treatment of 1. The binding interactions for 1 to NIK, XRCC-1, p53, XIAP, and caspase-1 proteins were explored in molecular docking studies. Additionally, the toxicity profile of 1 in zebrafish was favorable in comparison to its analog digoxin and other anticancer drugs at the same MTD in zebrafish. Overall, 1 targets the noncanconical NF-κB pathway in vivo and in vitro, and is well tolerated in zebrafish supporting its potential in the treatment of prostate cancer.     

Navitoclax Most Promising BH3 Mimetic for Combination Therapy in Hodgkin Lymphoma

The treatment of young patients with Hodgkin lymphoma (HL) is often successful but a significant proportion of patients suffers from late toxicity. In the current era there are new opportunities for less toxic and more targeted treatment options. In this respect, the anti-apoptotic pathway is an attractive target since Hodgkin tumor cells abundantly express components of this pathway. We measured the effect of BH3 mimetics that interfere with anti-apoptotic proteins in cell lines, also in combination with the standard of care chemotherapeutic doxorubicin and the recently discovered preclinically active tamoxifen. Several anti-apoptotic BCL-2 family proteins were expressed in each case (n = 84) and in HL cell lines (n = 5). Cell lines were checked for sensitivity to BH3 mimetics by BH3 profiling and metabolic assays and monotherapy was only partially successful. Doxorubicin was synergistic with a BCL-XL inhibitor and BCL2/XL/W inhibitor navitoclax. Tamoxifen that targets the estrogen receptor β present in the mitochondria of the cell lines, could induce cell death, and was synergistic with several BH3 mimetics including/as well as navitoclax. In conclusion, targeting the anti-apoptotic pathway by the triple inhibitor navitoclax in combination with doxorubicin or tamoxifen is a promising treatment strategy in HL.     

纳滤去除水中的有害离子

本文综述了纳滤去除饮用水和重金属废水中的有毒有害离子的应用研究,阐述了纳滤膜对无机盐的截留效果主要取决于膜对离子的电荷效应,表现在对多价离子的截留率高于单价离子。利用纳滤膜这种分离性能,可以去除部分饮用水中微量的有害单价离子（如NO2^-、NO3^-、F^-等）和大部分的有毒二价离子（如HAsO4^2-和重金属离子）,获取优质安全的饮用水;也可以用于处理重金属废水,能有效去除废水中的重金属离子。将纳滤和反渗透集成用于重金属废水处理,可以做到对有毒重金属离子的回收利用和出水回用,实现清洁生产,既具经济效益,又具环境效益,在工程实际中极具推广应用价值。