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PubMed2006

Suppression of Mycobacterium tuberculosis induced reactive oxygen species (ROS) and TNF-alpha mRNA expression in human monocytes by allicin.

Chronic inflammation associated with tumor necrosis factor (TNF)-alpha and reactive oxygen species (ROS) is the hallmark of tuberculosis. Mycobacterium tuberculosis (MTB) directly stimulates human monocytes to secrete TNF-alpha. We show the augmented expression of TNF-alpha mRNA in MTB-infected monocytes by cellular activation and ROS was suppressed by allicin in a dose-dependent manner. Also, allicin enhanced the glutathione peroxidase activity, which correlated inversely with the downregulation of ROS and TNF-alpha in MTB-infected monocytes. Hence, allicin may prove to be a valuable natural antioxidant in combating tuberculosis.

Base Sequence↗

PubMed2005

ROS mediates 4HPR-induced posttranscriptional expression of the Gadd153 gene.

All-trans-N-(4-hydroxyphenyl)retinamide (4HPR) is a synthetic retinoid that can induce apoptosis in many cancer cell lines. The cytotoxicity of 4HPR is dependent on the production of ROS but the underlying reasons are not entirely certain. We have investigated the role of 4HPR-induced production of ROS in mediating the expression of the recently identified 4HPR-responsive gene Gadd153. In 4HPR-treated cells, the elevation of Gadd153 protein level was prevented by vitamin C, which had no effect on the activation of the Gadd153 gene promoter. The 4HPR-induced elevation of Gadd153 mRNA level persisted even after transcription was blocked with actinomycin D, but declined rapidly upon the addition of antioxidants to the transcription-arrested cells. The mRNA expressed from the full-length Gadd153 cDNA was degraded constitutively in cells in the absence but not in the presence of 4HPR. Such an inhibitory effect of 4HPR was abolished by antioxidants and by inhibitors of 12-lipoxygenase, baicalein (specific) and esculetin (panspecific). The inhibition of 4HPR-induced expression of Gadd153 protein by vitamin C was independent of intracellular proteasome activity and vitamin C had no effect on the intracellular decay of Gadd153 protein. Our data provide the first evidence that the posttranscriptional expression of the Gadd153 gene can be regulated by ROS produced by 4HPR.

Antioxidants↗

PubMed2005

Elimination of major side effects due to ROS of therapeuticals through biotransformation control of the 57 cytochromes P450 isoenzymes.

Drug biotransformations are controlled in the body by tissue-differentiated choice of a selection of the induced and constitutive 57 isoforms of the human cytochromes P450 (CYP). CYP are the mixed function oxidase enzyme family (EC 1.14.14.1: mono-oxygenases that contain iron-dependent protohaematin IX). Many of the major side effects of clinical therapeutical agents have been attributed to the generation of highly toxic "reactive oxygen species" (ROS). Such ROS generation can be circumvented however by the ability to exert control over which forms of CYP are present: and as to which are bioactive in tissues other than the drug-target ones. Up to 57 isoenzymes of human cytochromes P450 are likely to be present: generation of a variety of species of ROS can be anticipated therefore with outcomes that include cancer, premature ageing, heart (arterial) damage and osteoporosis (in association with oestrogen/testosterone imbalance). Moreover, therapeutic vaccines could be constructed to remove the most harmful forms of cytochromes P450. Designer CYP protein enzymes can now be readily constructed by genetic engineering techniques: these include site-directed mutagenesis to place the modified cyp gene in suitable enzyme expression location in particular tissues only. Furthermore, gene therapy could be arranged to augment (or replace activities lost) for example the production of insulin in the Islets of Langerhans of the pancreas by production of the appropriate form of human insulin in the liver.

Biotransformation↗

PubMed2004

Generation of ROS in response to CCK-8 stimulation in mouse pancreatic acinar cells.

In the present study we have studied the changes in the intracellular reduction-oxidation state in mouse pancreatic acinar cells following stimulation with cholecystokinin octapeptide (CCK-8) and its dependence on Ca2+ mobilization. In our investigations cytosolic Ca2+ concentration and reactive oxygen species (ROS) production were determined by loading of cells with fura-2 and CM-H2DCF-DA, respectively. Changes in these parameters were determined by following changes in fluorescence in the cuvette of a spectrofluorimeter. The results show that stimulation of cells with CCK-8 and/or the sarco-endoplasmic reticulum Ca2+ pump inhibitor, thapsigargin (Tps), both induced changes in cytosolic free Ca2+ concentration and led to an increase in fluorescence of CM-H2DCF-DA, reflecting an increase in oxidation. In the presence of Tps, addition of CCK-8 did not significantly increase fluorescence compared to that evoked by the SERCA inhibitor. Similar results were obtained in the absence of extracellular Ca2+ and in the presence of EGTA. When the cells were challenged in the presence of the intracellular Ca2+ chelator BAPTA and in the absence of extracellular Ca2+ the responses to both CCK-8 and Tps were reduced although not completely inhibited. The mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxy-phenylhydrazone and the inhibitor of the electron transport chain, antimycin, evoked a marked increase in CM-H2DCF-DA fluorescence and completely inhibited CCK-8 and Tps-evoked responses, indicating that ROS are generated in the mitochondria. In summary, stimulation of mouse pancreatic acinar cells with CCK-8 leads to generation of ROS, and this effect may be derived from Ca2+ mobilization from intracellular stores and involves mitochondrial metabolism.

Journal Article↗

PubMed2006

Cross-linking of MHC class II molecules interferes with phorbol 12,13-dibutyrate-induced differentiation of resting B cells by inhibiting Rac-associated ROS-dependent ERK/p38 MAP kinase pathways leading to NF-kappaB activation.

In addition to their essential role in antigen presentation, major histocompatibility complex (MHC) class II molecules have been described as the receptor associated with signal transduction regulating B-cell function. In previous experiments, we found that cross-linking of MHC class II molecules with corresponding anti-MHC class II antibodies inhibited NF-kappaB-activated signaling pathways associated with the proliferation and differentiation of the LPS-stimulated primary and resting B-cell line, 38B9. We also found that exposure to the anti-MHC class II antibody reduced the production of ROS, which function as secondary signal transducers, in the phorbol 12,13-dibutyrate (PDBU)-treated (but not in the LPS-treated) resting B-cell line. In this study, we investigated the molecular mechanisms in the ROS-associated signaling pathway leading to PDBU-induced NF-kappaB activation that results in B-cell differentiation and speculated that the signaling pathway was inhibited by exposure to the anti-MHC class II antibody. We also found that this inhibition was mediated through down-regulation of the activated Rac/ROS-associated ERK/p38 MAPK signaling pathway in PDBU-treated 38B9 cells. Collectively, these findings suggest that ROS-associated molecules are involved in MHC class II-associated negative signal transduction in resting B cells.

Animals↗

PubMed2005

Cytotoxic effects of 100 reference compounds on Hep G2 and HeLa cells and of 60 compounds on ECC-1 and CHO cells. I mechanistic assays on ROS, glutathione depletion and calcein uptake.

In this study fluorometric assays have been used for medium throughput screening on toxicity. Dichlorofluorescein diacetate, monochlorobimane and calcein-AM were fluorophores for the measurement of the formation of reactive oxygen species (ROS), the quantification of glutathione and the membrane stability, respectively. These assays have been carried out in the presence or absence of toxic compounds and with four different cell lines, i.e. human liver (Hep G2), human endometrium (ECC-1), human cervix (HeLa) and Chinese hamster ovary cells (CHO). In these assays the toxic dose of 60 reference compounds was assessed for Hep G2, HeLa, ECC-1 and CHO cells and of 40 pharmaceutical compounds for Hep G2 (ROS, glutathione) or HeLa (calcein) cells, only. These compounds were narcotic analgesics, hypnotics, vasodilators, specific cellular energy blockers, cellular proliferation inhibitors, ion channel blockers, estrogens, antiestrogens, androgens, progestagens and others. The outcome of this study revealed that all four cell lines were responsive to the same set of drugs. Only for some drugs Hep G2 cells appear slightly more sensitive, as compared to the other three cell lines. In general the HeLa cell line was the most sensitive cell line for the calcein uptake, while the Hep G2 cell line shows slightly more sensitivity for dichorofluorescein and monochlorobimane assays than the other three cell lines. Further evaluation at higher toxic dosages with Hep G2 cells for ROS and glutathione depletion and HeLa cells for calcein uptake, demonstrated toxic effects for 56 of the 100 reference compounds in these assays, among which there were estrogens, androgens, progestagens and antiestrogens. In conclusion, almost all tested compounds gave similar dose and toxicity effects on the permanent cell lines used in this study. Only three compounds showed more tissue specific cell responses. This shows that in principle all four cell lines can be used for toxicity screening.

Animals↗

PubMed2006

NADPH oxidase-derived ROS: key modulators of heme-induced mitochondrial stability in human neutrophils.

Heme is a proinflammatory molecule able to cause a profound delay of constitutive apoptosis of human neutrophils, an effect that likely contributes to chronic inflammation associated with hemolytic diseases. Herein we show that heme-induced delay of neutrophil apoptosis correlates with the prevention of mitochondrial potential (Deltapsi(m)) dissipation by a mechanism dependent on NADPH oxidase (NADPHox)-generated reactive oxygen species (ROS) and NF-kappaB. Deltapsi(m) maintenance is accompanied by inhibition of Bax insertion into mitochondria and by a decrease in the Bad/Bcl-X(L) ratio. Heme induces Bad degradation in a completely ROS-dependent manner, as well as Bcl-X(L) synthesis, a phenomenon that also requires NF-kappaB activation. These data indicate that heme-induced preservation of mitochondrial integrity is a critical checkpoint controlled by NADPH oxidase generated-ROS and redox-sensitive NF-kappaB activation.

Apoptosis↗

PubMed2003

La(3+), Gd(3+) and Yb(3+) induced changes in mitochondrial structure, membrane permeability, cytochrome c release and intracellular ROS level.

Lanthanides (Ln) were known to induce cell apoptosis, which might be the results of their effects on mitochondria (MT). This study was trying to clarify the role of MT and reactive oxygen species (ROS) in Ln-induced apoptosis. We found that micromolar or lower concentration of La(3+), Gd(3+) and Yb(3+) bound to MT and induced swelling of isolated MT; EGTA treatment can inhibit the process. In addition, La(3+), Gd(3+) and Yb(3+) increased the MT membrane fluidity and decreased the MT membrane potential (DeltaPsi(m)). All these were inferred to the results of MT permeability transition pore opening. Release of cytochrome c (Cyt-c) from the MT upon incubation with Ln ions was monitored by immunocytochemistry, however, Cyt-c release was observed only in the cytosol of cells. In parallel with these events, there was a higher level of ROS found in the cells exposed to Ln. It was proposed that Ln-induced apoptosis via the MT pathways and it was highly possible that ROS were involved in the mechanism.

Animals↗

PubMed2003

Alpha2beta1-integrin signaling by itself controls G1/S transition in a human adenocarcinoma cell line (Caco-2): implication of NADPH oxidase-dependent production of ROS.

In this work, we report that type IV collagen, mainly via alpha2beta1-integrin ligation, was able to induce cyclin expression and G1/S transition in a colic adenocarcinoma cell line (Caco-2) cultured without soluble growth factors or fetal bovine serum. This process involved Erk 1/2 activation and the production of reactive oxygen species (ROS) by a membrane-bound NADPH oxidase. Data presented here show that NADPH oxidase-dependent production of ROS increased following alpha2beta1-integrin ligation with type IV collagen or with a specific monoclonal antibody (Gi9 mAb). NADPH oxidase activation and, therefore, the production of ROS were shown to be involved in the increase of alpha2beta1-integrin plasma membrane expression, p38 MAPK phosphorylation, cyclin expression, and G1/S transition. We thus identified in this work a new integrin-signaling pathway in colon tumor cells involved in cell cycle regulation by the extracellular matrix.

Adenocarcinoma↗

PubMed1987

Interaction of visual pigment with G-protein: effects of bleaching in native and reconstituted ROS preparations.

Native and reconstituted preparations of bullfrog rod outer segment (ROS) membranes were analysed for the binding of the alpha and beta subunits of G-protein. Following incubation at 22-28 degrees C under varying conditions of illumination and chemical treatment, preparations were chilled and extracted with hypotonic medium lacking-vs.-containing GTP (H and HG extracts, respectively). The extent of binding of G alpha,beta ('percentage G bound') was determined by measurement of the relative abundance of G alpha, beta in the H and HG extracts. The addition of G to unbleached, G-depleted membranes (D-ROS) yielded relatively little binding of the G (14 +/- 13%). G reintroduced at congruent to 1 min vs. congruent to 90 min after major bleaching yielded, respectively, levels of binding of 88 +/- 8% and 24 +/- 8%. Native G, extracted at congruent to 90 min post-bleach and added to freshly bleached D-ROS, exhibited binding exceeding that in the parent (bleached +90 min) sample. Supplementation of reconstituted suspensions with all-trans retinal, and subsequent incubation in darkness, yielded 30-35% G-binding; similar treatment with 11-cis retinal yielded binding in the range of 0-32%. Upon irradiation, suspensions previously supplemented with either isomer exhibited approximately 60% binding. Incubation with 11-cis retinal had no substantial effect on the condition of tight binding observed shortly after bleaching. The data are discussed in relation to previous studies of visual pigment bleaching and regeneration.

Animals↗

PubMed1993

Modulation of parathyroid hormone-sensitive adenylate cyclase in ROS 17/2.8 cells by dexamethasone 1,25-dihydroxyvitamin D3 and protein kinase C.

We tested whether the protein kinase C (PKC) modulation of PTH-sensitive adenylate cyclase in ROS 17/2.8 cells is affected by the glucocorticoid dexamethasone and the vitamin D hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Basal and PTH- and forskolin-stimulated adenylate cyclase activities were determined in the presence or absence of 100 nM phorbol 12-myristate 13-acetate (PMA), the activator of PKC, in ROS 17/2.8 cells that had been previously cultured with or without dexamethasone or 1,25(OH)2D3. Dexamethasone treatment increased the basal, PMA-, PTH-, (PTH + PMA)- and (forskolin + PMA)-sensitive adenylate cyclase while 1,25(OH)2D3 decreased these effects. The stimulatory and inhibitory effects were dose-dependent with respect to dexamethasone and 1,25(OH)2D3, respectively. Dexamethasone increased, while 1,25(OH)2D3 decreased the maximal activity of both PTH-sensitive and PKC-modulated PTH-sensitive adenylate cyclase without affecting the half-maximal concentration (ED50) of PTH required for the activation of the enzyme. Additionally, dexamethasone, 1,25(OH)2D3 and PKC did not affect each other's ED50. Our results suggest that the effects of dexamethasone, 1,25(OH)2D3 and PKC on PTH-sensitive adenylate cyclase in ROS 17/2.8 cells are independent of each other.

Adenylyl Cyclases↗

PubMed2003

Pulsed electromagnetic fields affect phenotype and connexin 43 protein expression in MLO-Y4 osteocyte-like cells and ROS 17/2.8 osteoblast-like cells.

Osteocytes, the predominant cells in bone, are postulated to be responsible for sensing mechanical and electrical stimuli, transducing signals via gap junctions. Osteocytes respond to induced shear by increasing connexin 43 (Cx43) levels, suggesting that they might be sensitive to physical stimuli like low-frequency electromagnetic fields (EMF). Immature osteoblasts exhibit decreased intercellular communication in response to EMF but no change in Cx43. Here, we examined long term effects of pulsed EMF (PEMF) on MLO-Y4 osteocyte-like cells and ROS 17/2.8 osteoblast-like cells. In MLO-Y4 cell cultures, PEMF for 8 h/day for one, two or four days increased alkaline phosphatase activity but had no effect on cell number or osteocalcin. Transforming growth factor beta-1 (TGF-beta 1) and prostaglandin E(2) were increased, and NO(2-) was altered. PEMFs effect on TGF-beta1 was via a prostaglandin-dependent mechanism involving Cox-1 but not Cox-2. In ROS 17/2.8 cells, PEMF for 24, 48 or 72 h did not affect cell number, osteocalcin mRNA or osteocalcin protein. PEMF reduced Cx43 protein in both cells. Longer exposures decreased Cx43 mRNA. This indicates that cells in the osteoblast lineage, including well-differentiated osteoblast-like ROS 17/2.8 cells and terminally differentiated osteocyte-like MLO-Y4 cells, respond to PEMF with changes in local factor production and reduced Cx43, suggesting decreased gap junctional signaling.

Alkaline Phosphatase↗

PubMed1998

Parathyroid hormone regulates the expression of the nuclear mitotic apparatus protein in the osteoblast-like cells, ROS 17/2.8.

The parathyroid hormone (PTH) signaling pathways that effect changes in osteoblast gene expression also alter the organization of the cytoskeletal proteins. PTH regulates the expression of nucleoskeletal proteins, such as nuclear mitotic apparatus protein (NuMA) and topoisomerase II-alpha. NuMA is a structural component of the interphase nucleus and organizes the microtubules of the mitotic spindle during mitogenesis. We propose that PTH-induced alterations in osteoblast cytoarchitecture are accompanied by changes in osteoblast nuclear structure that contribute to changes in gene expression. We used immunofluorescence and confocal microscopy to determine the effect of PTH on the expression and nuclear distribution of NuMA in the rat osteosarcoma cell line, ROS 17/2.8. Cells were treated with PTH or vehicle, then fixed and stained with NuMA antibody. Optical sections of interphase naive cells revealed a diffuse distribution of NuMA, interspersed with speckles, in the central nuclear planes but not in nucleoli. During the metaphase and anaphase, NuMA localized at the mitotic spindle apparatus. The percentage of NuMA-immunopositive ROS 17/2.8 cells decreased with increasing confluence, but serum starvation did not attenuate NuMA expression. Cell density-dependent changes in cytoskeletal organization were observed in these cells. PTH treatment induced changes in cytoskeletal organization and increased the percentage of NuMA-immunopositive ROS 17/2.8 cells. These data suggest that PTH effects changes in osteoblast nuclear architecture by regulating NuMA, and that these alterations may be coupled to cytoskeletal organization.

Animals↗

PubMed2006

A novel type of zinc finger DNA binding domain in the Agrobacterium tumefaciens transcriptional regulator Ros.

Transcriptional factors bearing a Cys(2)His(2) zinc finger were thought to be confined to eukaryotes, but recent studies have suggested their presence also in prokaryotes. In this paper, we report the first complete functional characterization of the DNA binding domain present in the putative Cys(2)His(2) zinc finger-containing prokaryotic transcriptional regulator Ros from Agrobacterium tumefaciens. We demonstrate that in the single zinc binding motif present in the Ros protein the metal ion is coordinated by two cysteines (Cys79 and Cys82) and two histidines (His92 and His97), separated by a shorter spacer with respect to the eukaryotic classical Cys(2)His(2) domains. The Cys(2)His(2) zinc finger motif is essential for Ros DNA binding and is part of a larger DNA binding domain which includes four basic regions located on either side of the finger, one at the N-terminus and three at the C-terminus. The one described here is a novel type of DNA binding domain containing a noncanonical Cys(2)His(2) zinc finger motif which, by sequence alignment, seems to be conserved in all the bacterial putative zinc finger proteins identified so far. Interestingly, basic amino acids have been shown to be important in stabilizing the DNA binding of eukaryotic single Cys(2)His(2) zinc finger domains, confirming that the modality of DNA binding using a single zinc finger motif flanked by basic residues is widespread throughout the living kingdom from eukaryotic, both animal and plant, to prokaryotic, even if in each kingdom it presents its peculiarity.

Agrobacterium tumefaciens↗

PubMed2004

Involvement of ROS and JNK1 in selenite-induced apoptosis in Chang liver cells.

Selenium is a dietary essential trace nutrient with important biological roles. Selenocompounds were reported to induce apoptosis in many types of tumor cells. In this study, we investigated the signaling pathway involved in the selenite-induced apoptosis using Chang liver cells as a non-malignant cell model. The Chang liver cell apoptosis induced by selenite (10 microM) was confirmed by DNA fragmentation and typical apoptotic nuclear changes. Treatment of selenite increased intracellular reactive oxygen species (ROS) level and c-Jun N-terminal kinase1 (JNK1) phosphorylation. The selenite-induced cell death was attenuated by SP600125, a specific inhibitor of JNK, and by dominant negative JNK1 (DN-JNK1). Antioxidants such as glutathione (GSH), N-acetyl cysteine (NAC), curcumin, epigallocatechin gallate (EGCG) and epicatechin (EC) inhibited selenite-induced intracellular ROS elevation and JNK1 phosphorylation. Our results suggest that selenite-induced apoptosis in Chang liver cells was preceded by the ROS generation and JNK1 activation.

Acetylcysteine↗

PubMed2004

Cell type-specific effects of asbestos on intracellular ROS levels, DNA oxidation and G1 cell cycle checkpoint.

Exposure to asbestos fibers increases the risk of development of mesotheliomas and lung carcinomas, but not fibrosarcomas. We present data suggesting that resistance of fibroblasts to asbestos-induced carcinogenesis is likely to be connected with their lower ability to generate reactive oxygen species (ROS) in response to asbestos exposure and stricter control of proliferation of cells bearing asbestos/ROS-induced injuries. In fact, chrysotile (Mg6Si4O10(OH)8) asbestos exposure (5-10 microg/cm2) increased intracellular ROS and 8-oxo-guanine contents in rat pleural mesothelial cells, but not in lung fibroblasts. Simultaneously, moderate dosages of chrysotile and other agents increasing ROS levels (hydrogen peroxide, H2O2 and ethyl-methanesulfonate, EMS) inhibited cell cycle progression, in particular G1-to-S transition, in fibroblasts, but not in mesothelial cells. The arrested fibroblasts underwent cell death, while the majority of chrysotile-treated mesothelial cells survived. The differences in cell cycle response to asbestos/ROS-induced injuries correlated with distinct activity of p53-p21Cip1/Waf1 pathway in the two cell types. Chrysotile, H2O2 and EMS caused p53 upregulation in both cell types, but mesothelial cells, unlike fibroblasts, showed no accumulation of p21Cip1/Waf1. Of note, treatment with doxorubicin caused similar p53-dependent p21Cip1/Waf1 upregulation and cell cycle arrest in both cell types. This suggests differential response of fibroblasts and mesothelial cells specifically to asbestos/ROS exposure rather than to all DNA-damaging insults.

Animals↗

PubMed2005

TGF beta1 induces prolonged mitochondrial ROS generation through decreased complex IV activity with senescent arrest in Mv1Lu cells.

Transforming growth factor beta1 (TGF beta1) is a well-characterized cytokine that suppresses epithelial cell growth. We report here that TGF beta1 arrested lung epithelial Mv1Lu cells at G1 phase of the cell cycle with acquisition of senescent phenotypes in the presence of 10% serum, whereas it gradually induced apoptosis with lower concentrations of serum. The senescent arrest was accompanied by prolonged generation of reactive oxygen species (ROS) and persistent disruption of mitochondrial membrane potential (DeltaPsim). We demonstrated that the sustained ROS overproduction was derived from mitochondrial respiratory defect via decreased complex IV activity and was involved in the arrest. Moreover, we verified that hepatocyte growth factor released Mv1Lu cells from the arrest by protecting mitochondrial respiration, thereby preventing both the DeltaPsim disruption and the ROS generation. Our present results suggest the TGF beta1-induced senescent arrest as another plausible mechanism to suppress cellular growth in vivo and provide a new biochemical association between the mitochondrial functional defects and the cytokine-induced senescent arrest, emphasizing the importance of maintenance of mitochondrial function in cellular protection from the arrest.

Animals↗

PubMed2005

Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS.

Most cancer therapeutics fails to eradicate cancer because cancer cells rapidly develop resistance to its proapoptotic effects. The underlying mechanisms remain incompletely understood. Here we show that three representative apoptotic stimuli, that is, serum starvation, a mitochondrial toxin, and a DNA-damaging agent (etoposide), rapidly induce several distinct classes of prosurvival molecules, in particular, Bcl-2/Bcl-X(L) and superoxide dismutase (SOD; including both MnSOD and Cu/ZnSOD). At the population level, the induction of these prosurvival molecules occurs prior to or concomitant with the induction of proapoptotic molecules such as Bim and Bak. Blocking the induction using siRNAs of the prosurvival or proapoptotic molecules facilitates or inhibits apoptosis, respectively. One master transcription factor, FOXO3a, is involved in the transcriptional activation of some of these prosurvival (e.g., MnSOD) and proapoptotic (e.g., Bim) molecules. Interestingly, in all three apoptotic systems, FOXO3a itself is also upregulated at the transcriptional level. Mechanistic studies indicate that reactive oxygen species (ROS) are rapidly induced upon apoptotic stimulation and that ROS inhibitors/scavengers block the induction of FOXO3a, MnSOD, and Bim. Finally, we show that apoptotic stimuli also upregulate prosurvival molecules in normal diploid human fibroblasts and at subapoptotic concentrations. Taken together, these results suggest that various apoptotic inducers may rapidly mobilize prosurvival mechanisms through ROS-activated master transcription factors such as FOXO3a. The results imply that effective anticancer therapeutics may need to combine both apoptosis-inducing and survival-suppressing strategies.

Apoptosis↗