共查询到20条相似文献,搜索用时 15 毫秒
1.
《Redox report : communications in free radical research》2013,18(1):13-22
AbstractThere is concern that dental-resin materials directly loaded on a prepared tooth adversely affect dental pulp tissue by releasing the resin chemicals through dentinal tubes. This study determined whether self-curing polymethyl methacrylate (PMMA)-based dental resin extract adversely affected the viability and function of odontoblast-like cells and whether the cytotoxicity of this resin, if any, could be eliminated by N-acetyl cysteine, an antioxidant amino acid derivative. Odontoblast-like cells isolated from rat maxillary incisor dental pulp tissue were exposed to a PMMA resin extract with or without N-acetyl cysteine for 1 h and then cultured in osteoblastic media. The percentage of viable cells 24 h after seeding was 20% in cells exposed to the resin extract without N-acetyl cysteine, whereas 45% of cells were viable after exposure to the N-acetyl cysteine-supplemented extract. The cells that had been exposed to the extract showed a strong tendency for apoptosis associated with the increased reactive oxygen species production and decreased intracellular glutathione level, which was improved by the addition of N-acetyl cysteine. N-Acetyl cysteine supplementation almost completely restored the significantly reduced alkaline phosphatase activity and matrix mineralization by the resin extract. These results conclusively demonstrated that exposure of odontoblast-like cells to the resin extract impaired the cell viability and function and, more intriguingly, N-acetyl cysteine supplementation to the extract significantly prevented these toxic effects. 相似文献
2.
Srabanti Rakshit Jayashree Bagchi Labanya Mandal Kausik Paul Dipyaman Ganguly Sandip Bhattacharjee Monidipa Ghosh Nabendu Biswas Utpal Chaudhuri Santu Bandyopadhyay 《Apoptosis : an international journal on programmed cell death》2009,14(3):298-308
Introduction Imatinib, a small-molecule inhibitor of the Bcr-Abl kinase, is a successful drug for treating chronic myeloid leukemia (CML).
Bcr-Abl kinase stimulates the production of H2O2, which in turn activates Abl kinase. We therefore evaluated whether N-acetyl cysteine (NAC), a ROS scavenger improves imatinib efficacy.
Materials and methods Effects of imatinib and NAC either alone or in combination were assessed on Bcr-Abl+ cells to measure apoptosis. Role of nitric oxide (NO) in NAC-induced enhanced cytotoxicity was assessed using pharmacological
inhibitors and siRNAs of nitric oxide synthase isoforms. We report that imatinib-induced apoptosis of imatinib-resistant and
imatinib-sensitive Bcr-Abl+ CML cell lines and primary cells from CML patients is significantly enhanced by co-treatment with NAC compared to imatinib
treatment alone. In contrast, another ROS scavenger glutathione reversed imatinib-mediated killing. NAC-mediated enhanced
killing correlated with cleavage of caspases, PARP and up-regulation and down regulation of pro- and anti-apoptotic family
of proteins, respectively. Co-treatment with NAC leads to enhanced production of nitric oxide (NO) by endothelial nitric oxide
synthase (eNOS). Involvement of eNOS dependent NO in NAC-mediated enhancement of imatinib-induced cell death was confirmed
by nitric oxide synthase (NOS) specific pharmacological inhibitors and siRNAs. Indeed, NO donor sodium nitroprusside (SNP)
also enhanced imatinib-mediated apoptosis of Bcr-Abl+ cells.
Conclusion NAC enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide. 相似文献
3.
Sodium butyrate (NaBu) is known to enhance the rate of biosynthesis of recombinant proteins in Chinese hamster ovary cells (CHO). Here we demonstrate that supplementation with NaBu during rapid growth brings about abrupt death of the cells. The death of the cells is due to apoptosis, as assessed by intranucleosomal DNA fragmentation. The promotion of apoptotic death of the cells could be partially blocked by treatment with the well-known antioxidant, N-acetylcysteine (NAC). Strikingly, the NAC treatment enhanced the production of recombinant EPO two-fold compared with that of the culture without NAC supplementation. These results showed that NaBu treatment supplemented with NAC not only inhibits apoptosis, but also exerts a synergistic effect on the biosynthesis of recombinant EPO. 相似文献
4.
Sodium butyrate (NaBu) is known to enhance the rate of biosynthesis of recombinant proteins in Chinese hamster ovary cells (CHO). Here we demonstrate that supplementation with NaBu during rapid growth brings about abrupt death of the cells. The death of the cells is due to apoptosis, as assessed by intranucleosomal DNA fragmentation. The promotion of apoptotic death of the cells could be partially blocked by treatment with the well-known antioxidant, N-acetylcysteine (NAC). Strikingly, the NAC treatment enhanced the production of recombinant EPO two-fold compared with that of the culture without NAC supplementation. These results showed that NaBu treatment supplemented with NAC not only inhibits apoptosis, but also exerts a synergistic effect on the biosynthesis of recombinant EPO. 相似文献
5.
Haiyan Wen Siqi Zhou Jinchun Song 《Biochemical and biophysical research communications》2019,508(4):1271-1278
Magnolol (Mag), an effective natural compound isolated from the stem bark of Magnolia officinalis, was found to have the potential for antitumor activity by inducing apoptosis in tumor cells. However, the effect of Mag on renal carcinoma cells and its molecular mechanism are unexplored. Our study provided evidence that Mag induced apoptosis in 786-O and OS-RC-2?cell lines via the mitochondrial pathway and cell cycle arrest. In this work, we found that Mag induced morphological changes and inhibited the proliferation of 786-O and OS-RC-2?cells in a dose- and time-dependent manner but exerted no notable inhibitory effects on normal human renal proximal tubular (HK-2) cells. Treatment with Mag suppressed the migration and invasion ability of renal carcinoma cells. Moreover, Mag caused the openness of mPTP, the accumulation of intracellular ROS and decreased △Ψm, leading to mitochondrial dysfunction. However, pretreatment with the antioxidant N-acetyl cysteine (NAC) reversed the apoptosis induced by Mag and decreased the generation of ROS. In addition, the increased proportion of the G1/G0 phase indicated that Mag caused cell cycle arrest. Further analyses suggested that magnolol-induced apoptosis was related to the abnormal expression of p53, Bax, Bcl-2, cytochrome c and caspase activation. Together, the results above revealed that Mag had antitumor effects in renal carcinoma cells via ROS production as well as cell cycle arrest and the apoptotic mitochondrial pathway was suppressed in part by NAC. 相似文献
6.
Nicoletti VG Marino VM Cuppari C Licciardello D Patti D Purrello VS Stella AM 《Neurochemical research》2005,30(6-7):737-752
Age-related increase of reactive oxygen species (ROS) is particularly detrimental in postmitotic tissues. Calorie restriction
(CR) has been shown to exert beneficial effects, consistent with reduced ROS generation by mitochondria. Many antioxidant
compounds also mimic such effects. N-acetyl cysteine (NAC) provides thiol groups to glutathione and to mitochondrial respiratory chain proteins; thus, it may
counteract both ROS generation and effects. In the present study we investigated, in different rat brain areas during aging
(6, 12, and 28 months), the effect of 1-year treatment with CR and dietary supplementation with NAC on the expression of subunit
39 kDa and ND-1 (mitochondrial respiratory complex I), subunit IV (complex IV), subunit α of F0F1-ATP synthase (complex V) and of adenine nucleotide translocator, isoform 1 (ANT-1). The observed age-related changes of expression
were prevented by the dietary treatments. The present study provides further evidence for the critical role of mitochondria
in the aging process. 相似文献
7.
Tributyltin-chloride, a well-known organotin compound, is a widespread environmental toxicant. The immunotoxic effects of tributyltin-chloride on mammalian system and its mechanism is still unclear. This study is designed to explore the mode of action of tributyltin-induced apoptosis and other parallel apoptotic pathways in murine thymocytes. The earliest response in oxidative stress followed by mitochondrial membrane depolarization and caspase-3 activation has been observed. Pre-treatment with N-acetyl cysteine and buthionine sulfoximine effectively inhibited the tributyltin-induced apoptotic DNA and elevated the sub G1 population, respectively. Caspase inhibitors pretreatment prevent tributyltin-induced apoptosis. Western blot and flow cytometry indicate no translocation of apoptosis-inducing factor and endonuclease G in the nuclear fraction from mitochondria. Intracellular Ca2+ levels are significantly raised by tributyltin chloride. These results clearly demonstrate caspase-dependent apoptotic pathway and support the role of oxidative stress, mitochondrial membrane depolarization, caspase-3 activation, and calcium during tributyltin-chloride (TBTC)-induced thymic apoptosis. 相似文献
8.
High dietary intakes and high blood levels of β-carotene are associated with a decreased incidence of various cancers. The anticancer effect of β-carotene is related to its pro-oxidant activity. DNA repair Ku proteins, as a heterodimer of Ku70 and Ku80, play a crucial role in DNA double-strand break repair. Reductions in Ku70/80 contribute to apoptosis. Previously, we showed that reactive oxygen species (ROS) activate caspase-3 which induces degradation of Ku proteins. In the present study, we investigated the mechanism of β-carotene-induced apoptosis of gastric cancer AGS cells by determining cell viability, DNA fragmentation, apoptotic indices (increases in cytochrome c and Bax, decrease in Bcl-2), ROS levels, mitochondrial membrane potential, caspase-3 activity, Ku70/80 levels, and Ku-DNA-binding activity of the cells treated with or without antioxidant N-acetyl cysteine and caspase-3 inhibitor z-DEVED-fmk. As a result, β-carotene induced apoptosis (decrease in cell viability, increases in DNA fragmentation and apoptotic indices) and caspase-3 activation, but decreased Ku70/80 levels and Ku-DNA-binding activity. β-Carotene-induced alterations (increase in caspase-3 activity, decrease in Ku proteins) and apoptosis were inhibited by N-acetyl cysteine and z-DEVED-fmk. Increment of intracellular and mitochondrial ROS levels and loss of mitochondrial membrane potential were suppressed by N-acetyl cysteine, but not by z-DEVED-fmk in β-carotene-treated cells. Therefore, β-carotene-induced increases in ROS and caspase-3 activity may lead to reduction of Ku70/80 levels, which results in apoptosis in gastric cancer cells. Loss of Ku proteins might be the underlying mechanism for β-carotene-induced apoptosis in gastric cancer cells. 相似文献
9.
《Free radical research》2013,47(3):338-346
AbstractPolycystic ovary syndrome (PCOS) is a common inflammatory and oxidant disease with an uncertain pathogenesis. N-acetyl cysteine (NAC) decreases oxidative stress, intracellular free calcium ion [Ca2+]i, and apoptosis levels in human neutrophil. We aimed to investigate the effects of NAC on apoptosis, oxidative stress, and Ca2+ entry through transient receptor potential vanilloid 1 (TRPV1) and TRP melastatin 2 (TRPM2) channels in neutrophils from patients with PCOS. Neutrophils isolated from PCOS group were investigated in three settings: (1) after incubation with TRPV1 channel blocker capsazepine or TRPM2 channel blocker 2-aminoethyl diphenylborinate (2-APB), (2) after supplementation with NAC (for 6 weeks), and (3) with combination (capsazepine + 2-APB + NAC) exposure. The neutrophils in TRPM2 and TRPV1 experiments were stimulated by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP; 1 μM) and capsaicin (10 μM) as concentration agonists, respectively. Neutrophil lipid peroxidation and capsaicin-induced increase in [Ca2+]i concentrations were reduced by capsazepine and NAC treatments. However, the [Ca2+]i concentration did not change by fMLP stimulation. Neutrophil lipid peroxidation, apoptosis, caspase-3, caspase-9, cytosolic reactive oxygen species production, and mitochondrial membrane depolarization values were decreased by NAC treatment although neutrophil glutathione peroxidase and reduced glutathione levels were increased by the NAC treatment. Serum lipid peroxidation, luteinizing hormone, testosterone, insulin, interleukin-1 beta, and homocysteine levels were decreased by NAC treatment although serum vitamin A, beta-carotene, vitamin E, and total antioxidant status were increased by the NAC treatment. In conclusion, NAC reduced oxidative stress, apoptosis, cytokine levels, and Ca2+ entry through TRPV1 channel, which provide supportive evidence that oxidative stress and TRPV1 channel plays a key role in etiology of PCOS. 相似文献
10.
Pyrrolizidine alkaloid (PA) clivorine, isolated from traditional Chinese medicinal plant Ligularia hodgsonii Hook, has been shown to induce apoptosis in hepatocytes via mitochondrial‐mediated apoptotic pathway in our previous research. The present study was designed to observe the protection of N‐acetyl‐cysteine (NAC) on clivorine‐induced hepatocytes apoptosis. Our results showed that 5 mM NAC significantly reversed clivorine‐induced cytotoxicity via MTT and Trypan Blue staining assay. DNA apoptotic fragmentation analysis and Western‐blot results showed that NAC decreased clivorine‐induced apoptotic DNA ladder and caspase‐3 activation. Further results showed that NAC inhibited clivorine‐induced Bcl‐xL decrease, mitochondrial cytochrome c release and caspase‐9 activation. Intracellular glutathione (GSH) is an important ubiquitous redox‐active reducing sulfhydryl (? SH) tripeptide, and our results showed that clivorine (50 µM) decreased cellular GSH amounts and the ratio of GSH/GSSG in the time‐dependent manner, while 5 mM NAC obviously reversed this depletion. Further results showed that GSH synthesis inhibitor BSO augmented clivorine‐induced cytotoxicity, while exogenous GSH reversed its cytotoxicity on hepatocytes. Clivorine (50 µM) significantly induced cellular reactive oxygen species (ROS) generation. Further results showed that 50 µM Clivorine decreased glutathione peroxidase (GPx) activity and increased glutathione S transferase (GST) activity, which are both GSH‐related antioxidant enzymes. Thioredoxin‐1 (Trx) is also a ubiquitous redox‐active reducing (? SH) protein, and clivorine (50 µM) decreased cellular expression of Trx in a time‐dependent manner, while 5 mM NAC reversed this decrease. Taken together, our results demonstrate that the protection of NAC is major via maintaining cellular reduced environment and thus prevents clivorine‐induced mitochondrial‐mediated hepatocytes apoptosis. J. Cell. Biochem. 108: 424–432, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
11.
(R)-2-(4′-Isobutylphenyl)propanoic acid (ibuprofen), (S)-3(4′-isobutylphenyl)butanoic acid and (S)-4-(4′-isobutylphenyl)pentanoic acid were obtained using microbial oxidation of (±)-l-isobutyl-4-(1′ -methyloctyl)benzene by Rhodococcus sp. BPM 1613. 相似文献
12.
13.
Massimiliano Monticone Angela Bisio Antonio Daga Paolo Giannoni Walter Giaretti Massimo Maffei Ulrich Pfeffer Francesco Romeo Rodolfo Quarto Giovanni Romussi Giorgio Corte Patrizio Castagnola 《Journal of cellular biochemistry》2010,111(5):1149-1159
Demethyl fruticulin A (SCO‐1) is a compound found in Salvia corrugata leaves. SCO‐1 was reported to induce anoikis in cell lines via the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36 showed that SCO‐1 was able to induce apoptosis also via alternative pathways. To gain some insight into the biological processes elicited by this compound, we undertook an unbiased genomic approach. Upon exposure of glioblastoma tumor initiating cells (GBM TICs) to SCO‐1 for 24 h, we observed a deregulation of the genes belonging to the glutathione metabolism pathway and of those belonging to the biological processes related to the response to stress and to chemical stimulus. On this basis, we hypothesized that the SCO‐1 killing effect could result from the induction of reactive oxygen species (ROS) in the mitochondria. This hypothesis was confirmed by flow cytometry using MitoSOX, a mitochondria‐selective fluorescent reporter of ROS, and by the ability of N‐acetyl cysteine (NAC) to inhibit apoptosis when co‐administered with SOC‐1 to the GBM TICs. We further show that NAC also protects other cell types such as HeLa, MG‐63, and COS‐7 from apoptosis. We therefore propose that ROS production is the major molecular mechanism responsible for the pro‐apoptotic effect induced by SCO‐1. Consequently, SCO‐1 may have a potential therapeutic value, which deserves further investigation in animal models. J. Cell. Biochem. 111: 1149–1159, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
14.
Min Ju Ryu Areum Daseul Kim Kyoung Ah Kang Ha Sook Chung Hye Sun Kim In Soo Suh Weon Young Chang Jin Won Hyun 《In vitro cellular & developmental biology. Animal》2013,49(1):74-81
This study investigated the mechanisms underlying the cytotoxicity of the green algae Ulva fasciata Delile. U. fasciata extract (UFE) inhibited the growth of HCT 116 human colon cancer cells by 50% at a concentration of 200 μg/ml. In addition, UFE stimulated the production of intracellular reactive oxygen species, an effect that was abolished by pretreatment with N-acetyl cysteine, which also inhibited the cytotoxic effects of UFE. UFE also induced morphological changes indicative of apoptosis, such as the formation of apoptotic bodies, DNA fragmentation, an increase in the population of apoptotic sub-G1 phase cells, and mitochondrial membrane depolarization. Concomitant activation of the mitochondria-dependent apoptotic pathway occurred via modulation of Bax and Bcl-2 expression, resulting in disruption of the mitochondrial membrane potential and activation of caspase-9 and caspase-3. This is the first report to demonstrate the cytotoxic effect of U. fasciata on human colon cancer cells and to provide a possible mechanism for this activity. 相似文献
15.
Foam cells derived from macrophages have been implicated as markers of early stage atherosclerosis development. In this study,
we found that N-acetyl cysteine (NAC), a well-known inhibitor of reactive oxygen species (ROS), decreased the generation of ROS and suppressed
foam cell formation in the presence of oxidized low density lipoprotein through down-regulation of cluster of differentiation
36 expression. We investigated gene expression profiles in order to determine the effects of NAC on foam cell formation using
a microarray analysis. The level of apolipoprotein E, which is involved in lipid efflux, was increased and the levels of the
antioxidant genes glutathione peroxidase 1 and 3 were also increased. The expression levels of the oxidative stress response
and the DNA repair genes were decreased. These results were confirmed using quantitative real-time PCR. Our results indicate
that oxidative stress plays an important role in foam cell formation, and that regulation of oxidation using antioxidants
is a potential therapeutic method for blocking atherosclerosis development. 相似文献
16.
Ben Wang Yifeng Shi Jiaoxiang Chen Zhenxuan Shao Libin Ni Yan Lin Yaosen Wu Naifeng Tian Yifei Zhou Liaojun Sun Aimin Wu Zhenghua Hong Xiangyang Wang Xiaolei Zhang 《Cell death & disease》2021,12(6)
Diabetes (DB) is a risk factor for osteoarthritis progression. High glucose (HG) is one of the key pathological features of DB and has been demonstrated to induce apoptosis and senescence in chondrocytes. Autophagy is an endogenous mechanism that can protect cells against apoptosis and senescence. The effects of HG on autophagy in cells including chondrocytes have been studied; however, the results have been inconsistent. The current study aimed to elucidate the underlying mechanisms, which could be associated with the contrasting outcomes. The present study revealed that HG can induce apoptosis and senescence in chondrocytes, in addition to regulating autophagy dynamically. The present study demonstrated that HG can cause oxidative stress in chondrocytes and suppress the AMPK pathway in a dose-dependent manner. Elimination of oxidative stress by Acetylcysteine, also called N-acetyl cysteine (NAC), downregulated autophagy and alleviated HG-stimulated apoptosis and senescence, while activation of the AMPK signaling pathway by AICAR not only upregulated autophagy but also alleviated HG-stimulated apoptosis and senescence. A combined treatment of NAC and AICAR was superior to treatment with either NAC or AICAR. The study has demonstrated that HG can suppress autophagy through the AMPK pathway and induce autophagy via oxidative stress in chondrocytes.Subject terms: Autophagy, Bone, Endocrine system and metabolic diseases 相似文献
17.
Mitchell L. Wise Hassan K. Sreenath Ronald W. Skadsen Heidi F. Kaeppler 《Plant Cell, Tissue and Organ Culture》2009,97(1):81-90
Oats produce a group of secondary metabolites termed avenanthramides (avn). These compounds are biosynthesized through the
action of the enzyme hydroxycinnamoyl CoA: hydroxyanthranilate N-hydroxycinnamoyl transferase (HHT) which catalyzes the condensation of one of several cinnamate CoA thioesters with the amine
functionality of anthranilic acid, 4-hydroxy- or 5-hydroxy-anthranilic acid. In oat leaf tissue the biosynthesis of avenanthramides
appears to result from elicitation by fungal infection. Here we demonstrate the biosynthesis of several avenanthramides in
suspension cultures of oat apical meristem callus tissue. This phenomenon appears as a generalized pathogen response, evidenced
by the production of PR-1 mRNA, in response to elicitation with chitin (poly-N-acetyl glucosamine). The suspension cultures also produce relatively large quantities of avnA and G in response to chitin
elicitation. Under certain culture conditions avnB and C are also produced as well as three additional metabolites tentatively
identified as avnH, O and R. These findings portend the utility of oat suspension culture as a tool for more detailed investigation
of the mechanisms triggering their biosynthesis as well as the factors dictating the particular types of avenanthramides biosynthesized. 相似文献
18.
Xuening Wang Alaa Dawod Matan Nachliely Jonathan S. Harrison Michael Danilenko George P. Studzinski 《Journal of cellular physiology》2020,235(1):573-586
Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D-based cell differentiation agents (doxercalciferol/carnosic acid [D2/CA]) added following the cytotoxic drug arabinocytosine (AraC) increases AML cell death (CD), a model for improved therapy of this disease. Because AraC-induced CD is known to involve reactive oxygen species (ROS) generation, here we investigated if the modulation of cellular REDOX status plays a role in the enhancement of cell death (ECD) by D2/CA. Using thiol antioxidants, such as N-acetyl cysteine (NAC), we found a significant inhibition of ECD, yet this occurred in the absence of any detectable change in cellular ROS levels. In contrast, NAC reduced the vitamin D receptor (VDR) abundance and its signaling of ECD. Importantly, VDR knockdown and NAC similarly inhibited ECD without producing an additive effect. Thus, the proposed post-AraC therapy may be compromised by agents that reduce VDR levels in AML blasts. 相似文献
19.
Ruifen Zhang Ian Humphreys Ravi P. Sahu Yan Shi Sanjay K. Srivastava 《Apoptosis : an international journal on programmed cell death》2008,13(12):1465-1478
Pancreatic cancer is one of the most common invasive malignancies and the fourth leading cause of cancer related mortality
in U.S., thus developing new strategies to control pancreatic cancer is an important mission. We investigated the mechanism
of capsaicin, the major pungent ingredient of red-chili pepper, in inducing apoptosis in pancreatic cancer cells. Treatment
of AsPC-1 and BxPC-3 cells with capsaicin resulted in a dose-dependent inhibition of cell-viability and induction of apoptosis
which was associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. These effects
were significantly blocked when the cells were pretreated with a general antioxidant N-acetyl cysteine (NAC). Exposure of AsPC-1 and BxPC-3 cells to capsaicin was also associated with increased expression of
Bax, down-regulation of bcl-2, survivin and significant release of cytochrome c and AIF in the cytosol. On the contrary, above-mentioned effects were not observed in the normal acinar cells in response
to capsaicin-treatment. Capsaicin-treatment resulted in the activation of JNK and JNK inhibitor SP600125 afforded protection
against capsaicin-induced apoptosis. Furthermore, capsaicin when given orally markedly suppressed the growth of AsPC-1 pancreatic
tumor xenografts in athymic nude mice, without side effects. Tumors from capsaicin treated mice demonstrated increased apoptosis,
which was related to the activation of JNK and increased cytosolic protein expression of Bax, cytochrome c, AIF and cleaved caspase-3, as compared with controls. Taken together, these results show that capsaicin is an effective
inhibitor of in vitro and in vivo growth of pancreatic cancer cells. These findings provide the rationale for further clinical
investigation of capsaicin against pancreatic cancer.
Ruifen Zhang and Ian Humphreys contributed equally to this work. 相似文献
20.
DNA damage signaling induced by the G-quadruplex ligand 12459 is modulated by PPM1D/WIP1 phosphatase
Céline Douarre Xénia Mergui Assitan Sidibe Dennis Gomez Patrizia Alberti Patrick Mailliet Chantal Trentesaux Jean-Fran?ois Riou 《Nucleic acids research》2013,41(6):3588-3599
The triazine derivative 12459 is a potent G-quadruplex ligand that triggers apoptosis or delayed growth arrest, telomere shortening and G-overhang degradation, as a function of its concentration and time exposure to the cells. We have investigated here the DNA damage response induced by 12459 in A549 cells. Submicromolar concentrations of 12459 triggers a delayed Chk1-ATR–mediated DNA damage response associated with a telomeric dysfunction and a G2/M arrest. Surprisingly, increasing concentrations of 12459 leading to cell apoptosis induced a mechanism that bypasses the DNA damage signaling and leads to the dephosphorylation of Chk1 and γ-H2AX. We identified the phosphatase Protein Phosphatase Magnesium dependent 1D/Wild-type P53-Induced Phosphatase (PPM1D/WIP1) as a factor responsible for this dephosphorylation. SiRNA-mediated depletion of PPM1D/WIP1 reactivates the DNA damage signaling by 12459. In addition, PPM1D/WIP1 is activated by reactive oxygen species (ROS) induced by 12459. ROS generated by 12459 are sufficient to trigger an early DNA damage in A549 cells when PPM1D/WIP1 is depleted. However, ROS inactivation by N-acetyl cysteine (NAC) treatment does not change the apoptotic response induced by 12459. Because PPM1D expression was recently reported to modulate the recruitment of DNA repair molecules, our data would suggest a cycle of futile protection against 12459, thus leading to a delayed mechanism of cell death. 相似文献