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

Because of possible side effects of herbal medicines containing ephedrine and guarana-derived caffeine, including increased risk of stroke, myocardial infarction, and sudden death, the Food and Drug Administration recently banned the sale of ephedra-containing products, specifically over-the-counter dietary supplements. We report cardiac in 7- and 14-week-old male F344 rats exposed by gavage to ephedrine(25 mg/kg) and caffeine (30 mg/kg) administered in combination for one or two days. The ephedrine-caffeine dosage was approximately 12- and 1.4-fold, respectively, above average human exposure, based on a mg/m2 body surface-area comparison. Several (5/7) of the exposed 14-week-old rats died or were sacrificed in extremis 4-5 h after the first dosing. In these hearts, changes were observed chiefly in the interventricular septum but also left and right ventricular walls. Massive interstitial hemorrhage, with degeneration of myofibers, occurred at the subendocardial myocardium of the left ventricle and interventricular septum. Immunostaining for cleaved caspase-3 and hyperphosphorylated H2A.X, a histone variant that becomes hyperphosphorylated during apoptosis, indicated multifocal generalized positive staining of degenerating myofibers and fragmenting nuclei, respectively. The Barbeito-Lopez trichrome stain revealed generalized patchy yellow myofibers consistent with degeneration and/or coagulative necrosis. In ephedrine-caffeine-treated animals terminated after the second dosing, foci of myocardial degeneration and necrosis were already infiltrated by mixed inflammatory cells. The myocardial necrosis may occur secondarily to intense diffuse vasoconstriction of the coronary arterial system with decreased myocardial perfusion. Our work shows the direct relationship between combined ephedrine and caffeine exposure and cardiac pathology.
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PMID:Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine. 1553 44

In the present study, we employed a well established JB6 mouse epithelial cell model to define the molecular mechanism of efficacy of a naturally occurring flavonoid silibinin against ultraviolet B (UVB)-induced skin tumorigenesis. UVB exposure of cells caused a moderate phosphorylation of ERK1/2 and Akt and a stronger phosphorylation of p53 at Ser(15), which was enhanced markedly by silibinin pretreatment. Kinase activity of ERK1/2 for Elk-1 and Akt for glycogen synthase kinase-3beta was also potently enhanced by silibinin pretreatment. Furthermore, silibinin increased the UVB-induced level of cleaved caspase 3 as well as apoptotic cells. Based on these observations, next we investigated the role of upstream kinases, ATM/ATR and DNA-PK, which act as sensors for UVB-induced DNA damage and transduce signals leading to DNA repair or apoptosis. Whereas UVB strongly activated ATM as observed by Ser(1981) phosphorylation, it was not affected by silibinin pretreatment. However, pretreatment of cells with the DNA-protein kinase (PK) inhibitor LY294002 strongly reversed silibinin-enhanced Akt-Ser(473) and p53-Ser(15) as well as ERK1/2 phosphorylation together with a dose-dependent decrease in cleaved caspase 3 and apoptosis (p < 0.05). In addition, silibinin pretreatment strongly enhanced H2A.X-Ser(139) phosphorylation and DNA-PK-associated kinase activity as well as the physical interaction of p53 with DNA-PK; pretreatment of cells with LY294002 but not caffeine abolished the silibinin-caused increase in both DNA-PK activation and p53-Ser(15) phosphorylations. Together, these findings suggest that silibinin preferentially activates the DNA-PK-p53 pathway for apoptosis in response to UVB-induced DNA damage, and that this could be a predominant mechanism of silibinin efficacy against UVB-induced skin cancer.
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PMID:Silibinin up-regulates DNA-protein kinase-dependent p53 activation to enhance UVB-induced apoptosis in mouse epithelial JB6 cells. 1579 56

Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson's drug, rasagiline, an irreversible and selective monoamine oxidase (MAO)-B inhibitor and its propargyl moiety, propargylamine. In cell death models induced by serum withdrawal in rat PC12 cells and human SH-SY5Y neuroblastoma cells, both rasagiline and propargylamine exerted neuroprotective and neurorescue activities via multiple survival pathways, including: stimulation of protein kinase C (PKC) phosphorylation; up-regulation of protein and gene levels of PKCalpha, PKCepsilon and the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w; and up-regulation of the neurotrophic factors, BDNF and GDNF mRNAs. Rasagiline and propargylamine inhibited the cleavage and subsequent activation of pro-caspase-3 and poly ADP-ribose polymerase. Additionally, these compounds significantly down-regulated PKCgamma mRNA and decreased the level of the pro-apoptotic proteins, Bax, Bad, Bim and H2A.X. Rasagiline and propargylamine both regulated amyloid precursor protein (APP) processing towards the non-amyloidogenic pathway. These structure-activity studies have provided evidence that propargylamine promoted neuronal survival via neuroprotective/neurorescue pathways similar to that of rasagiline. In addition, recent study demonstrated that chronic low doses of rasagiline administered to mice subsequently to 1 methyl-4 phenyl 1,2,3,6 tetrahydropyridine (MPTP), rescued dopaminergic neurons in the substantia nigra pars compacta via activation of the Ras-PI3K-Akt survival pathway, suggesting that rasagiline may possess a disease modifying activity.
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PMID:Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety. 1701 68

We recently reported that gallic acid is a major active agent responsible for grape seed extract activity in DU145 human prostate carcinoma cells. The present study was conducted to examine its efficacy and associated mechanism. Gallic acid treatment of DU145 cells resulted in a strong cell growth inhibition, cell cycle arrest, and apoptotic death in a dose- and time-dependent manner, together with a decrease in cyclin-dependent kinases and cyclins but strong induction in Cip1/p21. Additional mechanistic studies showed that gallic acid induces an early Tyr(15) phosphorylation of cell division cycle 2 (cdc2). Further upstream, gallic acid also induced phosphorylation of both cdc25A and cdc25C via ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) activation as a DNA damage response evidenced by increased phospho-histone 2AX (H2A.X) that is phosphorylated by ATM in response to DNA damage. Time kinetics of ATM phosphorylation, together with those of H2A.X and Chk2, was in accordance with an inactivating phosphorylation of cdc25A and cdc25C phosphatases and cdc2 kinase, suggesting that gallic acid increases cdc25A/C-cdc2 phosphorylation and thereby inactivation via ATM-Chk2 pathway following DNA damage that induces cell cycle arrest. Caffeine, an ATM/ataxia telangiectasia-rad3-related inhibitor, reversed gallic acid-caused ATM and H2A.X phosphorylation and cell cycle arrest, supporting the role of ATM pathway in gallic acid-induced cell cycle arrest. Additionally, gallic acid caused caspase-9, caspase-3, and poly(ADP)ribose polymerase cleavage, but pan-caspase inhibitor did not reverse apoptosis, suggesting an additional caspase-independent apoptotic mechanism. Together, this is the first report identifying gallic acid efficacy and associated mechanisms in an advanced and androgen-independent human prostate carcinoma DU145 cells, suggesting future in vivo efficacy studies with this agent in preclinical prostate cancer models.
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PMID:Gallic acid causes inactivating phosphorylation of cdc25A/cdc25C-cdc2 via ATM-Chk2 activation, leading to cell cycle arrest, and induces apoptosis in human prostate carcinoma DU145 cells. 1717 33

The anti-Parkinson, selective irreversible monoamine oxidase B inhibitor drug, rasagiline (Azilect), recently approved by the US Food and Drug Administration, has been shown to possess neuroprotective-neurorescue activities in in vitro and in vivo models. Recent preliminary studies indicated the potential neuroprotective effect of the major metabolite of rasagiline, 1-(R)-aminoindan. In the current study, the neuroprotective properties of 1-(R)-aminoindan were assessed employing a cytotoxic model of human neuroblastoma SK-N-SH cells in high-density culture-induced neuronal death. We show that aminoindan (0.1-1 mumol/L) significantly reduced the apoptosis-associated phosphorylated protein, H2A.X (Ser139), decreased the cleavage of caspase 9 and caspase 3, while increasing the anti-apoptotic proteins, Bcl-2 and Bcl-xl. Protein kinase C (PKC) inhibitor, GF109203X, prevented the neuroprotection, indicating the involvement of PKC in aminoindan-induced cell survival. Aminoindan markedly elevated pPKC(pan) and specifically that of the pro-survival PKC isoform, PKCepsilon. Additionally, hydroxyaminoindan, a metabolite of a novel bifunctional drug, ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], combining cholinesterase and monoamine oxidase inhibitor activity, exerted similar neuroprotective properties. Aminoindan and hydroxyaminoindan also protected rat pheochromacytoma PC-12 cells against the neurotoxin, 6-hydroxydopamine. Our findings suggest that both metabolites may contribute to the overall neuroprotective activity of their respective parent compounds, further implicating rasagiline and ladostigil as potentially valuable drugs for treatment of a wide variety of neurodegenerative disorders of aging.
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PMID:Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro. 1763 68

Accumulation of iron at sites where neurons degenerate in Parkinson's disease (PD) and Alzheimer's disease (AD) is thought to have a major role in oxidative stress induced process of neurodegeneration. The novel non-toxic lipophilic brain- permeable iron chelators, VK-28 (5- [4- (2- hydroxyethyl) piperazine-1-ylmethyl]- quinoline- 8- ol) and its multi-functional derivative, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), as well as the main polyphenol constituent of green tea (-)-epigallocatechin-3-gallate (EGCG), which possesses iron metal chelating, radical scavenging and neuroprotective properties, offer potential therapeutic benefits for these diseases. M-30 and EGCG decreased apoptosis of human SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via multiple protection mechanisms including: reduction of the pro-apoptotic proteins, Bad and Bax, reduction of apoptosis-associated Ser139 phosphorylated H2A.X and inhibition of the cleavage and activation of caspase-3. M-30 and EGCG also promoted morphological changes, resulting in axonal growth-associated protein-43 (GAP-43) implicating neuronal differentiation. Both compounds significantly reduced the levels of cellular holo-amyloid precursor protein (APP) in SH-SY5Y cells. The ability of theses novel iron chelators and EGCG to regulate APP are in line with the presence of an iron-responsive element (IRE) in the 5'-untranslated region (5'UTR) of APP. Also, EGCG reduced the levels of toxic amyloid-beta peptides in CHO cells over-expressing the APP "Swedish" mutation. The diverse molecular mechanisms and cell signaling pathways participating in the neuroprotective/neurorescue and APP regulation/processing actions of M-30 and EGCG, make these multifunctional compounds potential neuroprotective drugs for the treatment of neurodegenerative diseases, such as PD, AD, Huntington's disease and amyotrophic lateral sclerosis.
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PMID:Neurorescue activity, APP regulation and amyloid-beta peptide reduction by novel multi-functional brain permeable iron- chelating- antioxidants, M-30 and green tea polyphenol, EGCG. 1790 43

The isothiocyanate sulforaphane (SF) has been reported to possess chemopreventive efficiency towards various malignancies including colon cancer. Here, we investigated the antiproliferative and pro-apoptotic effects of SF on colon cancer cell line SW620. We found that SF at concentrations of 10-50 microM inhibits cell viability and proliferation of SW620 cells in a time- and dose-dependent manner, with IC50 being 26 microM (24 h), 24.4 microM (48 h) and 18 microM (72 h). Also, in the same cells SF caused DNA damage and chromatin condensation after 24 h and 48 h as revealed by phospho-H2A.X western blot analysis and DAPI staining of nuclei. These changes were accompanied by the elevated activity of caspase 3, although after 20 microM SF concentration only. Together, these results indicate that SF suppresses growth of human metastacic colonocytes and induces apoptotic cell death.
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PMID:In vitro antiproliferative effects of sulforaphane on human colon cancer cell line SW620. 1825 69

Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138(+) primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor-related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis.
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PMID:KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling. 1856 20

Curcumin has been shown to inhibit the growth of various types of cancer cells; however, at concentrations much above the clinically achievable levels in humans. The concentration of curcumin achieved in the plasma after oral administration in humans was estimated to be around 1.8 microM. Here, we report that treatment of BxPC-3 human pancreatic cancer cells with a low and single exposure of 2.5 microM curcumin for 24 h causes significant arrest of cells in the G2/M phase and induces significant apoptosis. Immunoblot studies revealed increased phosphorylation of H2A.X at Ser-139 and Chk1 at Ser-280 and a decrease in DNA polymerase-beta level in curcumin-treated cells. Phosphorylation of H2A.X and Chk1 proteins are an indicator of DNA damage whereas DNA polymerase-beta plays a role in the repair of DNA strand breaks. Normal immortalised human pancreatic ductal epithelial (HPDE-6) cells remained unaffected by curcumin treatment. In addition, we also observed a significant increase in the phosphorylation of Chk1 at Ser-345, Cdc25C at Ser-216 and a subtle increase in ATM phosphorylation at Ser-1981. Concomitant decrease in the expressions of cyclin B1 and Cdk1 were seen in curcumin-treated cells. Further, curcumin treatment caused significant cleavage of caspase-3 and PARP in BxPC-3 but not in HPDE-6 cells. Silencing ATM/Chk1 expression by transfecting BxPC-3 cells with ATM or Chk1-specific SiRNA blocked the phosphorylation of ATM, Chk1 and Cdc25C and protected the cells from curcumin-mediated G2/M arrest and apoptosis. This study reflects the critical role of ATM/Chk1 in curcumin-mediated G2/M cell cycle arrest and apoptosis in pancreatic cancer cells.
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PMID:Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells. 1940 1

Resveratrol, a phytoalexin, reduced the viability of MH7A cells, a human rheumatoid arthritis synovial cell line. In the apoptosis assay, resveratrol increased TUNEL-positive cells and stimulated H2A.X phosphorylation. Resveratrol disrupted mitochondrial membrane potentials in MH7A cells and stimulated cytochrome c release from the mitochondria to the cytosol. Resveratrol activated caspase-3 and caspase-9 but not caspase-8 in MH7A cells. Resveratrol upregulated the expression of the NAD-dependent deacetylase sirtuin 1 mRNA and downregulated the expression of the Bcl-X(L) mRNA, and resveratrol-induced MH7A cell death, mitochondrial damage, and caspase-3/-9 activation were prevented by sirtinol, an inhibitor of sirtuin 1. The results of the present study show that resveratrol induces MH7A cell apoptosis by activating caspase-9 and the effector caspase-3 along mitochondrial disruption as a result of reduced Bcl-X(L) expression, allowing cytochrome c release from the mitochondria into the cytosol, in a sirtuin 1-dependent manner. This suggests that resveratrol could suppress hyperplasia of synovial cells, a critical factor of rheumatoid arthritis.
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PMID:Resveratrol induces apoptosis MH7A human rheumatoid arthritis synovial cells in a sirtuin 1-dependent manner. 2069 95


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