Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzo(a)pyrene (BaP), a prototype of polycyclic aromatic hydrocarbons (PAHs), is a potent procarcinogen generated during the combustion of fossil fuels and cigarette smoke. In addition to the carcinogenic and mutagenic effects, BaP and other PAHs, including 7,12-dimethylbenz[a]anthracene and 2,3,7,8-tetrachlorodibenzo[p]dioxin, have been shown to induce programmed cell death or apoptosis. However, the molecular mechanisms by which PAHs such as BaP induce apoptosis are not clear. To investigate the molecular events leading to apoptosis induced by BaP, we studied the involvement of the interleukin 1beta-converting enzyme (ICE)/Ced-3 family of proteases (caspases) and c-Jun NH2-terminal kinase 1 (JNK1), which have been shown to mediate numerous extracellular stimuli-induced apoptosis. On treatment of mouse Hepa 1c1c7 hepatoma cells with BaP, the induction of apoptosis, as determined by genome digestion, was observed at concentrations of 1-30 microM after 24 h of treatments. Importantly, at the apoptosis-inducing concentrations, BaP also induced the activation of an ICE/Ced-3 cysteine protease caspase-3 but not caspase-1 (ICE). The activation of caspase-3 by BaP preceded apoptosis. Furthermore, a specific inhibitor of caspase-3-like proteases, acetyl-Asp-Glu-Val-Asp-aldehyde, significantly blocked caspase-3 activity and attenuated apoptosis induced by BaP. Treatment with BaP also caused a time- and dose-dependent activation of JNK1 activity. Interestingly, a much lower concentration (5 nM), as well as much earlier kinetics, were observed in JNK1 activation as compared with caspase-3 activation or induction of apoptosis by BaP. In summary, our results demonstrate that BaP induced apoptosis in the mouse hepatoma Hepa1c1c7 cell line via a caspase-dependent pathway, which may be independent of JNK activation.
 ...
PMID:Induction of apoptosis and activation of interleukin 1beta-converting enzyme/Ced-3 protease (caspase-3) and c-Jun NH2-terminal kinase 1 by benzo(a)pyrene. 960 52

Recently, we described a new in vivo pathway in the metabolism of benzo[a]pyrene (BP) that involves an opening of the aromatic ring system. One of the products of this pathway, isolated from rat urine, was the anhydride of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid (ABADA). We have now investigated the effect of ABADA on several cellular targets, known to be important in tumor formation. ABADA was as efficient as BP-7,8-diol-9,10-epoxide in inducing direct strand breaks but not alkali labile sites in DNA in HT-29 cells and exhibited weak mutagenic activity in Salmonella typhimurium strain TA 102. The cytotoxicity of ABADA to HCT 116 cells appeared to be due to apoptosis, as caspase-3 activity and poly-ADP-ribose polymerase (PARP) cleavage was observed. COX-2 promoter activity was induced by ABADA in HCT 116 cells. In conclusion, this novel metabolic pathway may also be contributing to the carcinogenicity of BP.
 ...
PMID:Toxicological characterization of a novel in vivo benzo[a]pyrene metabolite, 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid anhydride. 1238 25

Because benzo(a)pyrene (B(a)P)-coated onto hematite (Fe(2)O(3)) particle-induced adverse effects might alter cell homeostasis in lungs, we investigated the induction of some apoptotic events by such a concurrent exposure on this relevant organ target. Sprague-Dawley rats were intratracheally instilled with Fe(2)O(3) (3 mg), B(a)P (3 mg) or B(a)P (3 mg)-coated onto Fe(2)O(3) particles (3 mg). Forty-eight hours later, both the tumor necrosis factor-receptor and the mitochondrial pathways were studied. We found that exposure to B(a)P (1.13-fold, P<0.05) or to B(a)P-coated onto Fe(2)O(3) particles (1.15-fold, P<0.05) increased caspase 3 activity. However, only the concurrent exposure activated both the caspases 8 (1.21-fold, P<0.05) and 9 (1.27-fold, P<0.05). After exposure to either chemical alone, there was a discrepancy between the findings on tumor necrosis factor-alpha and caspase 8, on one hand, and on cytochrome c and caspase 9, on the other hand. Hence, we suggested that the oxidative stress induced by Fe(2)O(3) or B(a)P will continuously lower or deplete caspase activities, thereby reducing or even avoiding the activation of the apoptotic pathways. In addition, transcriptional induction of p53 gene by Fe(2)O(3) (1.73-fold, P<0.01) or B(a)P-coated onto Fe(2)O(3) particles (1.53-fold, P<0.01) was observed. Taken together, the present results support the underlying hypothesis that the influence of Fe(2)O(3) in B(a)P/Fe(2)O(3) mixtures on the ability of B(a)P to induce some of the events firmly involved in the apoptotic pathways will also be one of the ways that Fe(2)O(3) can affect B(a)P toxicity in lungs.
 ...
PMID:Benzo(a)pyrene-coated onto Fe2O3 particles-induced apoptotic events in the lungs of Sprague-Dawley rats. 1274 26

In this study we show that benzo[a]pyrene (B[a]P) and the cyclopenta polycyclic aromatic hydrocarbons (CP-PAH) cyclopenta[c,d]pyrene (CPP), benz[j]aceanthrylene (B[j]A) and benz[l]aceanthrylene (B[l]A) induce apoptosis in Hepa1c1c7 cells, as measured by fluorescence microscopy and flow cytometry. The compounds induced formation of the active form of caspase-3, cleavage of its intracellular substrate, poly(ADP-ribose)polymerase (PARP), and DNA fragmentation. B[j]A was found to be the most potent in inducing apoptosis, followed by B[a]P, CPP and B[l]A. All compounds increased expression of CYP1A1 with relative potencies B[j]A > B[a]P >> CPP > B[l]A, corresponding well with their relative apoptotic responses. alpha-Naphthoflavone (alphaNF), an inhibitor of CYP1A1, reduced the induced apoptosis. B[a]P and CP-PAH exposure also resulted in an accumulation of the tumour suppressor protein p53. No changes were observed in the protein levels of Bax and Bcl-2, whereas the anti-apoptotic Bcl-xl protein was down-regulated, as judged by western blot analysis. Fluorescence microscopic analysis revealed a translocation of p53 to the nucleus and of Bax to the mitochondria. Furthermore, caspase-8 was activated and Bid cleaved. Interestingly, the levels of anti-apoptotic phospho-Bad (Ser155 and Ser112) had a biphasic increase after B[a]P or CPP treatment. Whereas alphaNF markedly reduced the activation of B[a]P to reactive metabolites, as measured by covalent binding to macromolecules, it did not inhibit the up-regulation of phospho-Bad. Neither of the compounds triggered apoptosis in primary cultures of rat lung cells (Clara cells, type 2 cells and lung alveolar macrophages), possibly due to a lack of CYP1A1 induction. In conclusion, B[a]P and the CP-PAH induced apoptotic as well as anti-apoptotic signals in Hepa1c1c7 cells.
 ...
PMID:Polycyclic aromatic hydrocarbons induce both apoptotic and anti-apoptotic signals in Hepa1c1c7 cells. 1472 87

Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants. Previously, clinical studies have shown a significant chemopreventive efficacy of ATB against human esophageal and lung cancers. In the present study, A/J mice harboring a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf and treated with benzo[a]pyrene were used to investigate the chemopreventive effects of ATB on chemically induced lung tumorigenesis. Mice with various genotypes treated with ATB displayed a significant reduction in lung tumor multiplicity and tumor load. Treatment with ATB resulted in an approximately 40% decrease in tumor multiplicity and a 70% decrease in tumor load in both wild-type mice and in mice with a loss of the Ink4a/Arf tumor suppressor genes. Interestingly, ATB decreased tumor multiplicity and volume by 50 and 90%, respectively, in mice with a dominant-negative p53 and in mice with both a p53 mutation and deletion of Ink4a/Arf. Kras2 mutation analysis of the lung tumors revealed that tumors harbored mutations in the 12th codon of Kras2. There were no differences in either the incidence or types of mutations between tumors treated with or without ATB. Oligonucleotide array analysis revealed 284 genes that were differentially expressed in mouse lung tumors as compared to the normal lung, and it was found that 114 out of these 284 genes changed their expression toward the normal levels in tumors treated with ATB. Most of the genes modulated by ATB belong to several cellular signaling pathways, including Notch (Notch homolog 2, manic fringe homolog), growth factor (FGF intracellular-binding protein, PDGFalpha), G protein-Ras-MAPK (MAPK3, MAP3K4, rab3A, Rap1, RSG5, PKCtheta), ubiquitin-proteasome (CDC34, Cullin1, 26S proteasome), and apoptosis (BAD promoter, caspase 3). These results suggest that ATB is an effective chemopreventive against mouse lung tumorigenesis. Furthermore, ATB exhibited an enhanced inhibitory effect in animals harboring genetic alterations (Kras2, p53, and Ink4a/Arf), which are often seen in human lung adenocarcinomas.
 ...
PMID:Cancer chemopreventive activity of a mixture of Chinese herbs (antitumor B) in mouse lung tumor models. 1502 4

Benzo(a)pyrene (BaP), a potent carcinogen, has been shown to induce apoptosis via activation of caspase-3. However, the upstream of caspase-3 and other apoptosis signaling remain to be elusive. Herein, we demonstrated that treatment of Hepa1c1c7 cells with BaP increased the transcriptional expression of aryl hydrocarbon nuclear transporter and cytochrome p450 1A1 in a time and dose-dependent manner but did not aromatic hydrocarbon receptor. Also, the catalytic activation of caspase-3 and caspase-9 was induced whereas that of caspase-3 and caspase-9 was not by the addition of BaP. BaP also induced the mitochondrial dysfunction, including transition of mitochondria membrane potential and cytosolic release of cytochrome c. Furthermore, a decrease in the expression of Bcl-2 to Bax ratio and phosphorylation of p53(Ser 15) were observed in BaP-treated cells. Taken together, these results demonstrated that BaP-induced apoptosis of Hepa1c1c7 cells via activation of intrinsic caspase pathway including caspase-3, caspase-9, with mitochondrial dysfunction and p53 activation.
 ...
PMID:Benzo(a)pyrene-induced apoptotic death of mouse hepatoma Hepa1c1c7 cells via activation of intrinsic caspase cascade and mitochondrial dysfunction. 1512 97

We have shown previously that naturally occurring isothiocyanates derived from cruciferous vegetables and their N-acetylcysteine conjugates inhibit lung adenoma formation induced by tobacco carcinogens in A/J mice at the post-initiation stage. The tumor-inhibitory activity by these compounds is linked with activation of activator protein and induction of apoptosis in lung tissues, suggesting that these compounds may also inhibit the development of adenomas to adenocarcinomas in lung. In this study, the chemopreventive activity of phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates during progression of lung adenomas to malignant tumors was investigated in A/J mice. Mice were divided into 14 groups and treated with a mixture of 3 micromol benzo(a)pyrene [B(a)P] and 3 micromol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) given by gavage once weekly for 8 weeks. Twenty weeks after the beginning of carcinogen administration, a total of 20 mice in the treatment groups were sacrificed with an average yield of 7.3 +/- 4.5 lung adenomas per mouse. The remaining mice in each group were fed diets containing phenethyl isothiocyanate (3 and 1.5 mmol/kg diet), sulforaphane (3 and 1.5 mmol/kg diet), phenethyl isothiocyanate-N-acetylcysteine (8 and 4 mmol/kg diet), sulforaphane-N-acetylcysteine (8 and 4 mmol/kg diet) during weeks 21 to 42. Four mice in each of the high-dose treatment groups were sacrificed during weeks 28 and 36 and the bioassay was terminated during week 42; lung tissues were harvested for histopathologic examination of tumors and for cell proliferation (proliferating cell nuclear antigen) and apoptosis (caspase-3) assays using immunohistochemical staining. At termination, the incidence of adenocarcinoma in the 3 mmol/kg diet phenethyl isothiocyanate group and 8 mmol/kg diet phenethyl isothiocyanate-N-acetylcysteine group was reduced to 19% and 13%, respectively, compared with 42% in the carcinogen-treated control group. At the lower doses, phenethyl isothiocyanate and its N-acetylcysteine conjugate also inhibited the incidences of lung adenocarcinoma, however, the decreases were not statistically significant. The lung tumor incidences in groups treated with sulforaphane-N-acetylcysteine in the diet were also significantly reduced to 11% or 16%. Furthermore, the malignant lung tumor multiplicity was significantly reduced from 1.0 tumor/mouse in the carcinogen-treated control group to 0.3 in the sulforaphane low-dose group, 0.3 and 0.4 in the two sulforaphane-N-acetylcysteine groups, and 0.4 in the phenethyl isothiocyanate high-dose group. The malignant tumor multiplicities in other treatment groups were also reduced (0.5-0.8 tumors/mouse), but not significantly. Unlike lung adenocarcinomas, both incidences and multiplicities of lung adenomas were not much affected by treatment with isothiocyanates or their conjugates. Immunohistochemical examination of the lung tumors from all time points indicated that significant reduction in proliferating cell nuclear antigen and induction of apoptosis (terminal nucleotidyl transferase-mediated nick end labeling and caspase-3) were observed in the isothiocyanate and isothiocyanate-N-acetylcysteine-treated groups that showed inhibition of the development of lung adenocarcinomas. The results of the study provide a basis for future evaluation of the potential of phenethyl isothiocyanate and sulforaphane and their conjugates as chemopreventive agents in smokers and ex-smokers with early lung lesions.
 ...
PMID:Phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A/J mice. 1616 36

Polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP), are widespread in the environment and cause untoward effects, including carcinogenesis, in mammalian cells. However, the molecular mechanism of apoptosis by BaP is remained to be elusive. Pharmacological inhibition of p38 kinase markedly inhibited the BaP-induced cytotoxicity, which was proven as apoptosis characterized by an increase in sub-G(0)/G(1) fraction of DNA content, ladder-pattern fragmentation of genomic DNA, and catalytic activation of caspase-3 with PARP cleavage. Our data also demonstrated that activation of caspase-3 was accompanied with activation of caspase-9 and mitochondrial dysfunction, which was also apparently suppressed by pretreatment with p38 kinase inhibitors. Also, pharmacological inhibition of p38 markedly inhibited the phosphorylation, accumulated expression, and transactivation activity of p53 in BaP-treated cells. Adenoviral overexpression of human p53 (wild-type) further augmented in increase of PARP cleavage and the sub-G(0)/G(1) fraction of DNA content. Furthermore, p53 mediated apoptotic activity in BaP-treated cells was inhibited by p38 kinase inhibitor. The current data collectively indicate that BaP induces apoptosis of Hepa1c1c7 cells via activation of p53-related signaling, which was, in part, regulated by p38 kinase.
 ...
PMID:p38 MAP kinase regulates benzo(a)pyrene-induced apoptosis through the regulation of p53 activation. 1629 69

Spices and flavoring plants part rich in supposedly health-promoting phytochemicals are currently receiving much attention as a possible source of cancer chemopreventive compounds. Clove, the sun-dried unopened flower bud from the plant Syzygium aromaticum L. is a commonly used spice and food flavor. In the present work we assess the chemopreventive potential of aqueous infusion of clove during benzo[a]pyrene (BP)-induced lung carcinogenesis in strain A mice. Incidence of hyperplasia, dysplasia and carcinoma in situ evident in the carcinogen control group on the 8th, 17th and 26th weeks, respectively, were effectively reduced after treatment with clove infusion. Significant reduction in the number of proliferating cells and an increased number of apoptotic cells was also noted in these BP-induced lung lesions following clove treatment. Western blotting analysis revealed that clove infusion upregulates the expression of pro-apoptotic proteins p53 and Bax, and downregulates the expression of anti-apoptotic protein Bcl-2 in the precancerous stages. Expression of caspase 3 and its activation by clove infusion were evident from a very early stage of carcinogenesis (eighth week). Clove infusion was also found to downregulate the expression of some growth-promoting proteins, viz, COX-2, cMyc, Hras. The observations signify the chemopreventive potential of clove in view of its apoptogenic and anti-proliferative properties.
 ...
PMID:Clove (Syzygium aromaticum L.), a potential chemopreventive agent for lung cancer. 1650 Dec 50

Exogenous treatment with monosialoganglioside GM1 has been described to afford protection against different apoptotic insults. However, the underlying mechanisms remain to be determined. In this study, we focused on the effect of GM1 on the apoptotic cascade induced by benzo[a]pyrene (B[a]P) in rat hepatic F258 epithelial cells. We first demonstrated that a co-treatment with GM1 (80 microM) reduced B[a]P (50 nM)-induced apoptosis as evidenced by a decrease of both cell population exhibiting nuclear fragmentation and caspase 3 cleavage and activity. We next showed that the p53 phosphorylation and nuclear translocation as well as the intracellular alkalinization related to Na+/H+ exchanger 1 (NHE1) activation, two early events of the apoptosis induced by B[a]P, were not inhibited by GM1. In contrast, the late mitochondria-dependent acidification elicited by B[a]P was inhibited by GM1 co-treatment, and an inhibition of the oxidative stress was also observed. Because GM1 has been shown to reduce the low-molecular weight iron content related to ethanol-induced oxidative stress, we finally investigated the involvement of iron under our conditions. Using the two iron chelators deferiprone and desferrioxamine, we clearly showed that iron played an important role in B[a]P-induced apoptosis in F258 cells, and that B[a]P-treatment resulted in a significant GM1-sensitive increase in (55)Fe uptake. In conclusion, our results indicate that exogenous GM1 partly prevents B[a]P-induced apoptosis by interfering with mitochondria-related intracellular acidification and iron transport.
 ...
PMID:Protective effect of monosialoganglioside GM1 against chemically induced apoptosis through targeting of mitochondrial function and iron transport. 1696 73


1 2 3 4 5 6 Next >>