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High‐performance liquid chromatographic enantioseparation of N‐aryl‐thioureidoalkylphosphonates and thiourylenedi(alkylphosphonates) on polysaccharide‐based chiral stationary phases
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Józef Drabowicz Marcin H. Kudzin Zbigniew H. Kudzin Patrycja Pokora‐Sobczak 《Chirality》2018,30(2):131-140
The first successful enantioseparation of representative O,O‐diphenyl‐N‐arylthioureidoalkylphosphonates, (±)‐Ptc‐ValP(OPh)2 & (±)‐Ptc‐LeuP(OPh)2 and thiourylenedi(isobutyl phosphonate), Tcm[ValP(OPh)2]2 on analytical and semipreparative scale was achieved by high‐performance liquid chromatography using polysaccharide‐based chiral stationary phases (CPs). Atc‐AAP(OPh)2 was obtained using modified tricomponent condensations of the corresponding aldehydes, N‐arylthiourea and triphenyl phosphite whereas Tcm[ValP(OPh)2]2 by the condensations of aldehydes, thiourea, and triphenyl phosphite. The prepared, racemic (±)‐Atc‐AAP(OPh)2 [(±)‐Ptc‐ValP(OPh)2, (±)‐Ptc‐LeuP(OPh)2, (±)‐Ptc‐PglyP(OPh)2 and (±)‐Ntc‐PglyP(OPh)2] and racemic (±)‐Tcm[AAP(OPh)2]2 [(±)‐Tcm[NvaP(OPh)2]2 & (±)‐Tcm[ValP(OPh)2]2] were adequately characterized and used for chromatographic separations on high‐performance liquid chromatography–chiral stationary phases. The best results were obtained for (±)‐Ptc‐ValP(OPh)2, (±)‐Ptc‐LeuP(OPh)2 and (±)‐Tcm[ValP(OPh)2]2. 相似文献
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Suberoyl bishydroxamic acid (SBHA) is a HDAC inhibitor that can regulate many biological functions including apoptosis and proliferation in various cancer cells. Here, we evaluated the effect of SBHA on the growth of HeLa cervical cancer cells in relation to apoptosis, reactive oxygen species (ROS) and glutathione (GSH) levels. Dose-dependent inhibition of cell growth was observed in HeLa cells with an IC50 of approximately 15 μM at 72 h. SBHA also induced apoptosis in HeLa cells, as evidenced by sub-G1 cells, annexin V-FITC staining cells, activations of caspase 3 and 8, and the loss of mitochondrial membrane potential (ΔΨm). In addition, all of the tested caspase inhibitors rescued some cells from SBHA-induced HeLa cell death. SBHA increased ROS levels including O 2 ?? and induced GSH depletion in HeLa cells. Generally, caspase inhibitors did not affect ROS levels in SBHA-treated HeLa cells, but they significantly prevented GSH depletion in these cells. Furthermore, while the well-known antioxidants, N-acetyl cysteine and vitamin C, did not affect cell death, ROS level or GSH depletion in SBHA-treated HeLa cells, l-buthionine sulfoximine, a GSH synthesis inhibitor, enhanced cell death and GSH depletion in these cells. In conclusion, SBHA inhibits the growth of HeLa cervical cancer cells via caspase-dependent apoptosis, and the inhibition is independent of ROS level changes, but dependent on GSH level changes. 相似文献
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Ayodeji A. Agbowuro Jimin Hwang Emma Peel Rami Mazraani Alexandra Springwald James W. Marsh Laura McCaughey Allan B. Gamble Wilhelmina M. Huston Joel D.A. Tyndall 《Bioorganic & medicinal chemistry》2019,27(18):4185-4199
Chlamydia trachomatis high temperature requirement A (CtHtrA) is a serine protease that performs proteolytic and chaperone functions in pathogenic Chlamydiae; and is seen as a prospective drug target. This study details the strategies employed in optimizing the irreversible CtHtrA inhibitor JO146 [Boc-Val-Pro-ValP(OPh)2] for potency and selectivity. A series of adaptations both at the warhead and specificity residues P1 and P3 yielded 23 analogues, which were tested in human neutrophil elastase (HNE) and CtHtrA enzyme assays as well as Chlamydia cell culture assays. Trypsin and chymotrypsin inhibition assays were also conducted to measure off-target selectivity. Replacing the phosphonate moiety with α-ketobenzothiazole produced a reversible analogue with considerable CtHtrA inhibition and cell culture activity. Tertiary leucine at P3 (8a) yielded approximately 33-fold increase in CtHtrA inhibitory activity, with an IC50 = 0.68 ± 0.02 µM against HNE, while valine at P1 retained the best anti-chlamydial activity. This study provides a pathway for obtaining clinically relevant inhibitors. 相似文献
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Background
This study evaluated the cytotoxic activity of extracts from Caesalpinia sappan heartwood against multiple cancer cell lines using an MTT cell viability assay. The cell death though induction of apoptosis was as indicated by DNA fragmentation and caspase-3 enzyme activation.Results
A methanol extract from C. sappan (MECS) showed cytotoxic activity against several of the cancer cell lines. The most potent activity exhibited by the MECS was against HeLa cells with an IC50 value of 26.5 ± 3.2 μg/mL. Treatment of HeLa cells with various MECS concentrations resulted in growth inhibition and induction of apoptosis, as indicated by DNA fragmentation and caspase-3 enzyme activation.Conclusion
This study is the first report of the anticancer properties of the heartwood of C. sappan native to Vietnam. Our findings demonstrate that C. sappan heartwood may have beneficial applications in the field of anticancer drug discovery. 相似文献6.
BackgroundBiogenic nanoparticles are gaining attention due to their low toxicity and numerous biomedical applications. Present study aimed to compare the potential anticancer activity of two biogenic silver nanoparticles (bAgNPs and pAgNPs) against human cervical cancer cell lines (HeLa).MethodsbAgNPs were synthesized using Acinetobacter sp. whereas pAgNPs were synthesized using aqueous root extract of Curcuma aromatica. Effect of these nanoparticles on HeLa cells viability was studied using MTT assay and colony formation assay. Anticancer potential was determined using fluorescence microscopy and flow cytometry studies. Bio-compatibility studies were performed against peripheral blood mononuclear cells (PBMCs).ResultsBoth the nanoparticles showed 50 % viability of peripheral blood mononuclear cells (PBMCs) when used at high concentration (200 μg/mL). IC50 for bAgNPs and pAgNPs against HeLa cells were 17.4 and 14 μg/mL respectively. Colony formation ability of Hela cells was reduced on treatment with both nanoparticles. Acridine orange and ethidium bromide staining demonstrated that bAgNPs were cytostatic whereas pAgNPs were apoptotic. JC-1 dye staining revealed that the mitochondrial membrane potential was affected on treatment with pAgNPs while it remained unchanged on bAgNPs treatment. Flow cytometry confirmed cell cycle arrest in HeLa cells on treatment with nanoparticles further leading to apoptosis in case of pAgNPs. About 77 and 58 % HeLa cells were found in subG1 phase on treatment with bAgNPs and pAgNPs respectively. bAgNPs showed cytostatic effect on HeLa cells arresting the cell growth in subG1 phase, whereas, pAgNPs triggered death of HeLa cells through mitochondrial membrane potential impairment and apoptosis.ConclusionOverall, bAgNPs and pAgNPs could be safe and showed potential to be used as anticancer nano-antibiotics against human cervical cancer cells. 相似文献
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An Antimicrobial Peptidomimetic Induces Mucorales Cell Death through Mitochondria-Mediated Apoptosis
E. Magda Barbu Fazal Shirazi Danielle M. McGrath Nathaniel Albert Richard L. Sidman Renata Pasqualini Wadih Arap Dimitrios P. Kontoyiannis 《PloS one》2013,8(10)
The incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in fungi. Our group has previously designed and developed a proteolytically-resistant peptidomimetic motif D(KLAKLAK)2 with pleiotropic action ranging from targeted (i.e., ligand-directed) activity against cancer and obesity to non-targeted activity against antibiotic resistant gram-negative rods. Here we evaluated whether this non-targeted peptidomimetic motif is active against Mucorales. We show that D(KLAKLAK)2 has marked fungicidal action, inhibits germination, and reduces hyphal viability. We have also observed cellular changes characteristic of apoptosis in D(KLAKLAK)2-treated Mucorales cells. Moreover, the fungicidal activity was directly correlated with vacuolar injury, mitochondrial swelling and mitochondrial membrane depolarization, intracellular reactive oxygen species accumulation (ROS), and increased caspase-like enzymatic activity. Finally, these apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine indicating mechanistic pathway specificity. Together, these findings indicate that D(KLAKLAK)2 makes Mucorales exquisitely susceptible via mitochondrial injury-induced apoptosis. This prototype may serve as a candidate drug for the development of translational applications against mucormycosis and perhaps other fungal infections. 相似文献
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《Peptides》2015
Buforin IIb, a novel cell-penetrating anticancer peptide derived from histone H2A, has been reported to induce mitochondria-dependent apoptosis in tumor cells. However, increasing evidence suggests that endoplasmic reticulum and mitochondria cooperate to signal cell death. In this study, we investigated the mechanism of buforin IIb-induced apoptosis in human cervical carcinoma HeLa cells by focusing on ER stress-mediated mitochondrial membrane permeabilization. Two-dimensional PAGE coupled with MALDI-TOF and western blot analysis showed that buforin IIb treatment of HeLa cells resulted in upregulation of ER stress proteins. PBA (ER stress inhibitor) and BAPTA/AM (Ca2+ chelator) pretreatment rescued viability of buforin IIb-treated cells through abolishing phosphorylation of SAPK/JNK and p38 MAPK. SP600125 (SAPK/JNK inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated down-regulation of Bcl-xL/Bcl-2, mitochondrial translocation of Bax, and cytochrome c release from mitochondria. Taken together, our data suggest that the ER stress pathway has an important role in the buforin IIb-induced apoptosis in HeLa cells. 相似文献
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Margarethe Draga Elizabeth B. Madgett Cassandra J. Vandenberg David du Plessis Aisling Kaufmann Petra Werler Prasun Chakraborty Noel F. Lowndes Kevin Hiom 《Molecular and cellular biology》2015,35(22):3829-3840
The Fanconi anemia DNA repair pathway is pivotal for the efficient repair of DNA interstrand cross-links. Here, we show that FA-defective (Fancc−) DT40 cells arrest in G2 phase following cross-link damage and trigger apoptosis. Strikingly, cell death was reduced in Fancc− cells by additional deletion of the BRCA1 tumor suppressor, resulting in elevated clonogenic survival. Increased resistance to cross-link damage was not due to loss of toxic BRCA1-mediated homologous recombination but rather through the loss of a G2 checkpoint. This proapoptotic role also required the BRCA1-A complex member ABRAXAS (FAM175A). Finally, we show that BRCA1 promotes G2 arrest and cell death by prolonging phosphorylation of Chk1 on serine 345 after DNA damage to sustain arrest. Our data imply that DNA-induced cross-link death in cells defective in the FA pathway is dependent on the ability of BRCA1 to prolong cell cycle arrest in G2 phase. 相似文献
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Nazlihan Aztopal Didem Karakas Buse Cevatemre Ferda Ari Ceyda Icsel Maria G. Daidone Engin Ulukaya 《Bioorganic & medicinal chemistry》2017,25(1):269-276
Recent accumulating evidence has supported the notion that tumors have hierarchically organized heterogeneous cell populations and a small subpopulation of cells, termed cancer stem cells (CSCs), are responsible for tumor initiation, maintenance as well as drug resistance. Therefore, targeting the CSCs along with the other cancer cells has been the most important topic during the last decade. In the present study, we evaluated the cytotoxic activity of trans-[PtCl2(2-hepy)2] [2-hepy = 2-(2-hydroxyethyl) pyridine] complex and the mechanism of cell death in breast CSCs. Stemness markers, Oct-4 and Sox2, were determined in mammospheres by western blotting. Cytotoxicity was assessed using the ATP viability assay. Cell death was fluorescently visualized and further confirmed by flow cytometry as well as gene expression analysis. The Pt(II) complex significantly reduced the cell viability, prevented mammosphere formation and disrupted mammosphere structures in a dose-dependent manner (0–100 μM). The mode of cell death was apoptosis and it was shown by the presence of caspase 3/7 activity, Annexin V-FITC positivity, decreased mitochondrial membrane potential and increased expressions of pro-apoptotic genes (TNFRSF10A and HRK). Interestingly, necroptosis was also observed by the evidence of increased MLKL expression. In conclusion, the Pt(II) complex seems to be a highly promising anticancer compound due to its promising cytotoxic activity on CSCs. Therefore, it deserves in vivo further studies for the proof-of-concept. 相似文献
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The advances in the treatment of chronic myeloid leukemia (CML) during the last years were also accompanied by the development of evading strategies by tumor cells, resulting in chemotherapy resistance in some patients. Patented organopalladium compounds derived from the reaction of N,N-dimethyl-1-phenethylamine (dmpa) with [1,2-ethanebis(diphenylphosphine)] (dppe) exhibited a potent antitumor activity in vivo and in vitro in melanoma cells. We showed here that the cyclopalladated derivative [Pd2(R(+))C2, N-dmpa)2(μ-dppe)Cl2], named compound 7b, was highly effective to promote cell death in the K562 human leukemia cells and its mechanisms of action were investigated. It was shown that compound 7b was able to promote exclusively apoptotic cell death in K562 cells associated to cytochrome c release and caspase 3 activation. This cytotoxic effect was not observed in normal peripheral mononuclear blood cells. The compound 7b-induced intrinsic apoptotic pathway was triggered by the protein thiol oxidation that resulted in the dissipation of the mitochondrial transmembrane potential. The preventive effect of the dithiothreitol on the compound 7b-induced cell death and all downstream events associated to apoptosis confirmed that death signal was elicited by the thiol oxidation. These findings contribute to the elucidation of the palladacycle 7b-induced cell death mechanism and present this compound as a promising drug in the CML antitumor chemotherapy. 相似文献
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Pardaxin, a pore-forming antimicrobial peptide that encodes 33 amino acids was isolated from the Red Sea Moses sole, Pardachirus mamoratus. In this study, we investigated its antitumor activity in human fibrosarcoma (HT-1080) cells and epithelial carcinoma (HeLa) cells. In vitro results showed that the synthetic pardaxin peptide had antitumor activity in these two types of cancer cells and that 15 μg/ml pardaxin did not lyse human red blood cells. Moreover, this synthetic pardaxin inhibited the proliferation of HT1080 cells in a dose-dependent manner and induced programmed cell death in HeLa cells. DNA fragmentation and increases in the subG1 phase and caspase 8 activities suggest that pardaxin caused HeLa cell death by inducing apoptosis, but had a different mechanism in HT1080 cells. 相似文献
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Dimethylfumarate (DMF) is cytotoxic to several kinds of cells and serves as an anti-tumor drug. This study was designed to investigate the effects and underlying mechanism of DMF on cervical cancer cells. HeLa cells were cultured and treated with 0, 50, 100, 150, and 200 μM DMF, respectively. After 24 h, cell growth was evaluated using Cell Counting Kit-8 (CCK-8) assay and the cell cycle was examined using flow cytometry. In addition, cell apoptosis was detected by Annexin V/propidium iodide (PI) staining and the expressions of caspase-3 and poly-ADP-ribose polymerase (PARP) were detected using western blotting. The redox-related factors were then assessed. Furthermore, all of the indicators were detected in HeLa cells after combined treatment of DMF and N-acetyl-l-cysteine (NAC, an oxygen-free radical scavenger). The cell number and cell growth of HeLa were obviously inhibited by DMF in a dose-dependent manner, as the cell cycle was arrested at G0/G1 phase (P?<?0.05). The apoptotic HeLa cells were markedly increased, and the expression levels of caspase-3 and PARP were significantly increased in a DMF concentration-dependent way (P?<?0.05). Meanwhile, loss of △Ψm, increase in reactive oxygen species and O2 ·?, and the decrease in catalase activity and glutathione (GSH) level were found after DMF treatment (P?<?0.05). All these changes were significantly attenuated and even completely disappeared by adding NAC (P?<?0.05). In conclusion, the cytotoxicity of DMF on cell proliferation and apoptosis of HeLa cells was mainly related to the intracellular redox systems by depletion of intracellular GSH. 相似文献
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Manuel Sandoval Robert A. Ronzio Dave N. Muanza David A. Clark Mark J.S. Miller 《Nitric oxide》1997,1(6):476-483
Peroxynitrite (ONOO−) has been proposed as a mediator of gut inflammation and as an inducer of cell death by apoptosis. Phytolens (PHY), a water-soluble extract of polyphenolic antioxidants from nonsoy legumes (Biotics Research Corp, patent pending), was evaluated as a cytoprotective agent in human colonic (T84) and murine macrophage (RAW 264.7) cell lines. In the antioxidant testing, PHY showed a significant free radical scavenging ability against 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and superoxide (O2•) radicals with an IC50of 4.44 and 5.87 μg/ml against DPPH and O2•, respectively. Apoptosis (DNA fragmentation) was measured by an ELISA technique. Cells were exposed to oxidative stress by treating them with peroxynitrite (100–300 μM) for 4 h in the presence and absence of PHY. Peroxynitrite elicited a dose-dependent increase in DNA fragmentation in both cell lines compared to the control group receiving decomposed ONOO−. PHY (10, 30, or 50 μg/ml) significantly attenuated the degree of apoptosis in T84 cells induced by ONOO−(P< 0.05). PHY (10–100 μg/ml) did not directly affect T84 cell viability or induce apoptosis after 4 h or overnight exposure. RAW 264.7 cells exposed to PHY alone (>30 μg/ml) for 4 h displayed decreased cell viability (P< 0.05) and increased apoptosis (P< 0.05). Phytolens may have beneficial effects on inflammation by attenuating peroxynitrite-induced apoptosis. The sparing of epithelial cells while compromising the viability of macrophages suggests that PHY may be beneficial in autoimmune disorders. 相似文献
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Duane Gischewski Pereira Mariana Manzano Rendeiro Vanessa Faria Cortes Leandro Augusto Barbosa Luis Eduardo M. Quintas 《Journal of cellular biochemistry》2019,120(8):13107-13114
Despite the growing interest in the antitumor effect of cardiotonic steroids, combination treatments with well-established chemotherapy drugs like paclitaxel have been rarely investigated. Moreover, paclitaxel has been suggested as a Na+/K+-ATPase inhibitor. Here we investigated the effect of paclitaxel and digoxin alone or in combination on the viability of human lung (A549) and cervical cancer (HeLa) cell lines and the inhibitory effect of paclitaxel on several mammalian Na+/K+-ATPases. Although the viability of both tumor cell lines was concentration-dependently affected by digoxin treatment after 48 hours (A549 IC50 = 31 nM and HeLa IC50 = 151 nM), a partial effect was observed for paclitaxel, with a maximal inhibitory effect of 45% at 1000 nM with A549 and around 70% with HeLa cells (IC50 = 1 nM). Although the two drugs were cytotoxic, their combined effect in HeLa cells was revealed to be antagonistic, as estimated by the combination index. No direct inhibitory effect of paclitaxel was detected in human, pig, rat, and mouse Na+/K+-ATPase enzymes, but high concentrations of paclitaxel decreased the Na+/K+-ATPase activity in HeLa cells after 48 hours without affecting protein expression. Our findings demonstrate that, under our conditions, paclitaxel and digoxin cotreatment produce antagonistic cytotoxic effects in HeLa cells, and the mechanism of action of paclitaxel does not involve a direct inhibition of Na+/K+-ATPase. More studies shall be designed to evaluate the consequences of the interaction of cardiotonic steroids and chemotherapy drugs. 相似文献
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Gunasekar Manoharan Seema R. Jaiswal Jaipaul Singh 《Molecular and cellular biochemistry》2014,388(1-2):233-240
A multitude of plants have been used extensively for the treatment of cancers throughout the world. The protein, α, β momorcharin has been extracted from the plant Momordica charantia (MC), and it possesses anti-cancer and anti-HIV properties similar to the crude water and methanol soluble extract of the plant. This study investigated the anti-cancer effects and the cellular mechanisms of action of α, β momocharin (200–800 μM) on 1321N1, Gos-3, U87-MG, Sk Mel, Corl-23 and Weri Rb-1 cancer cell lines compared to normal healthy L6 muscle cell line measuring cell viability using MTT assay kit, Caspase-3 and 9 activities, cytochrome c release and intracellular free calcium concentrations [Ca2+]i. The results show that α, β momorcharin can evoke significant dose-dependent (P < 0.05; Student’s t test) decreases in the viability (increases in cell death) of 1321N1, Gos-3, U87-MG, Sk Mel, Corl-23 and Weri Rb-1 cancer cell lines compared to healthy L6 muscle cell line and untreated glioma cells. α, β momorcharin (800 μM) also evoked significant (P < 0.05) increases in caspase-3 and 9 activities and cytochrome c release. Similarly, α, β momorcharin elicited significant (P < 0.05) time-dependent elevation in [Ca2+]i in all five glioma cell lines compared to untreated cells. Together, the results have demonstrated that α, β momorcharin can exert its anti-cancer effect on different cancer cell lines by intracellular processes involving an insult to the mitochondria resulting in cellular calcium over loading, apoptosis, cytochrome release and subsequently, cell death. 相似文献
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Xiangyi Ma Ling Xi Danfeng Luo Ronghua Liu Shu Li Yan Liu Liangsheng Fan Shuangmei Ye Wanhua Yang Shuhong Yang Li Meng Jianfeng Zhou Shixuan Wang Ding Ma 《PloS one》2012,7(9)
The treatment of cancer such as oligonucleotides or peptides requires efficient delivery systems. A novel peptide, TMTP1, previously derived and identified in our laboratory showed remarkable ability to target highly metastatic tumors both in vitro and in vivo, even at the early stage of occult metastasis foci. TMTP1 moderately inhibited tumor cell viability, although not enough to deem it an efficient killer of tumor cells. In this study, we sought to enhance the anti-tumor activity of TMTP1. To do this, we fused it to an antimicrobial peptide, D(KLAKLAK)2, and termed the resulting peptide TMTP1-DKK. We found that TMTP1-DKK could trigger rapid apoptosis in human prostate and gastric cancer cells through both the mitochondrial-induced apoptosis pathway and the death receptor pathway. Furthermore, direct injection of TMTP1-DKK into mice with prostate and gastric xenograft cancers resulted in reduction of tumor volumes and a significant delay in tumor progression and metastasis in vivo. These results suggest that TMTP1-DKK may serve as a powerful therapeutic agent for metastatic tumors. 相似文献
18.
Sa?d Taouji Arisa Higa Frédéric Delom Sandrine Palcy Fran?ois-Xavier Mahon Jean-Max Pasquet Roger Bossé Bruno Ségui Eric Chevet 《The Journal of biological chemistry》2013,288(24):17190-17201
In BCR-ABL-expressing cells, sphingolipid metabolism is altered. Because the first step of sphingolipid biosynthesis occurs in the endoplasmic reticulum (ER), our objective was to identify ABL targets in the ER. A phosphoproteomic analysis of canine pancreatic ER microsomes identified 49 high scoring phosphotyrosine-containing peptides. These were then categorized in silico and validated in vitro. We demonstrated that the ER-resident human protein serine palmitoyltransferase long chain-1 (SPTLC1), which is the first enzyme of sphingolipid biosynthesis, is phosphorylated at Tyr164 by the tyrosine kinase ABL. Inhibition of BCR-ABL using either imatinib or shRNA-mediated silencing led to the activation of SPTLC1 and to increased apoptosis in both K562 and LAMA-84 cells. Finally, we demonstrated that mutation of Tyr164 to Phe in SPTLC1 increased serine palmitoyltransferase activity. The Y164F mutation also promoted the remodeling of cellular sphingolipid content, thereby sensitizing K562 cells to apoptosis. Our observations provide a mechanistic explanation for imatinib-mediated cell death and a novel avenue for therapeutic strategies. 相似文献
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Endothelial cells (EC) are subject to oxidative-induced cell death. Activation of poly(ADP-ribose) polymerase (PARP) occurs early in oxidant-induced EC injury and putatively mediates cell death by depleting its substrate, NAD+. In this study, the role of PARP in H2O2-induced EC death was investigated. EC were exposed to oxidant stress and viability continuously monitored using fluorescent dye exclusion. Inhibition of PARP with 1,5-dihydroxyisoquinoline (DIQ) delayed the time course of oxidant-induced EC death. Concurrent addition of the protein synthesis inhibitor, cycloheximide, or the endonuclease inhibitor, aurintricarboxylic acid, to PARP-inhibited cells further delayed the onset and attenuated the extent of H2O2-induced cell lysis, consistent with an active mode of cell death. Caspase-3-like activity, a hallmark of apoptosis, was negligible in oxidant-treated EC alone, however, inhibition of PARP by 3-aminobenzamide or DIQ dramatically increased caspase-3-like activity. Morphological assessment confirmed that the primary mode of death in oxidant-stressed EC was oncosis. However, following PARP inhibition, the cells switched to apoptosis. Since inflammation is associated with oncosis and not apoptosis, the results presented here could explain the beneficial effects seen with PARP inhibition in various in vivo models of oxidant injury and provide a mechanism to manipulate this injury into a state of cell death that could ultimately be controlled. 相似文献