Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

1,25-Dihydroxyvitamin D3 (1,25D3) exhibits potent antitumor activity in the murine squamous cell carcinoma (SCC) SCCVII/SF, and the combination of 1,25D3 with cisplatin (1,25D3/cisplatin) demonstrates even greater activity. Because these agents possess different mechanisms of cytotoxicity, studies were initiated to define the mechanism by which the combination displays enhanced activity. Median dose-effect analysis demonstrates that 1,25D3 and cisplatin act synergistically to inhibit SCC growth. When SCC cells were treated with 1,25D3 (10 nM) and/or cisplatin (0.5 microg/ml), greater caspase-3 activation was observed for the combination than for either agent alone. This suggests that the enhanced cytotoxicity is, at least in part, due to greater induction of apoptosis. No alterations in cellular platinum concentration or platinum-DNA adducts were observed for 1,25D3/cisplatin cotreatment compared with cisplatin treatment alone. Effects of the combination on cisplatin and 1,25D3 signaling pathways in adherent (nonapoptotic) and floating (apoptotic) cells were explored. Cisplatin induced p53 and its downstream targets, p21(Cip1) (p21) and Bax, in both cell populations. In contrast, 1,25D3 reduced p53, p21, and Bax to nearly undetectable levels in adherent cells. In the floating cells, 1,25D3 reduced levels of p53 and p21, but Bax expression was maintained at control levels. Expression of these proteins in cells treated with 1,25D3/cisplatin was similar to treatment with 1,25D3 alone. The two agents also had divergent effects on survival and stress signaling pathways. Phospho-extracellular signal-regulated kinase 1/2 and phospho-Jun levels increased after treatment with cisplatin but decreased after treatment with 1,25D3 and 1,25D3/cisplatin. Moreover, cisplatin decreased levels of mitogen-activated protein kinase kinase kinase (MEKK-1), whereas 1,25D3 up-regulated MEKK-1, and 1,25D3/cisplatin further up-regulated MEKK-1. We propose that the increased cytotoxicity for 1,25D3/cisplatin results from cisplatin enhancement of 1,25D3-induced apoptotic signaling through MEKK-1.
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PMID:Cisplatin potentiates 1,25-dihydroxyvitamin D3-induced apoptosis in association with increased mitogen-activated protein kinase kinase kinase 1 (MEKK-1) expression. 1249 15

Photodynamic therapy (PDT) may trigger apoptosis or necrosis in cancer cells. Several steps in the induction and execution of apoptosis require high amounts of adenosine-5'-triphosphate (ATP). Because the mitochondrial membrane potential (delta psi) decreases early in apoptosis, we raised the question about the mechanisms of maintaining a sufficiently high ATP level. We therefore monitored delta psi and the intracellular ATP level of apoptotic human epidermoid carcinoma cells (A431) after photodynamic treatment with aluminum (III) phthalocyanine tetrasulfonate. A maximum of caspase-3-like activity and nuclear fragmentation was found at fluences of about 4 J cm(-2). Under these conditions apoptotic cells reduced delta psi rapidly, while the ATP level remained high for 4-6 h after treatment for cells supplied with glucose. To analyze the contribution of glycolysis to the energy supply during apoptosis, experiments were carried out with cells deprived of glucose. These cells showed a rapid drop of ATP content and neither caspase activation nor nuclear fragmentation could be detected. We conclude that the use of glucose as a source of ATP is obligatory for the execution of PDT-induced apoptosis.
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PMID:Glucose is required to maintain high ATP-levels for the energy-utilizing steps during PDT-induced apoptosis. 1251 Oct 53

Photodynamic therapy (PDT) is a kind of photochemo-therapeutic treatment that exerts its effect mainly through the induction of cell death. Distinct types of cell death may be elicited by different PDT regimes. In this study, the mechanisms involved in the death of human epidermoid carcinoma A431 cells triggered by PDT with Photofrin (a clinically approved photosensitizer) were characterized. Photofrin distributes dynamically in A431 cells; the plasma membranes and Golgi complex are the main target sites of Photofrin after a brief (3 h) and prolonged (24 h) incubation, respectively. Cells with differentially localized Photofrin displayed distinct death phenotypes in response to PDT. The effects of PDT on cells with plasma membrane-localized Photofrin were further studied in details. Cells stopped proliferating post PDT at Photofrin dose >7 micro g/ml, and at higher dose (28 micro g/ml) plasma membrane disruption and cell swelling were observed immediately after PDT. Dramatic alterations of several important signaling events were detected in A431 cells post Photofrin-PDT, including (i) immediate formation of reactive oxygen species (ROS), (ii) rapid activation of c-Jun N-terminal kinase, (iii) delayed activation of caspase-3 and cleavage of polyADP-ribose polymerase and p21-activated kinase 2, and (iv) loss of mitochondrial membrane potential. Intriguingly, the characteristics of typical apoptosis such as phosphatidylserine externalization and DNA fragmentation were not detected in the cell death process caused by this PDT regime. In conclusion, our results show that when plasma membranes are the main targets, Photofrin-PDT can lead to instant ROS formation and subsequent activation of downstream signaling events similar to those elicited by many apoptotic stimuli, but the damage of plasma membranes renders the death phenotype more necrosis like.
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PMID:Subcellular localization of Photofrin determines the death phenotype of human epidermoid carcinoma A431 cells triggered by photodynamic therapy: when plasma membranes are the main targets. 1254 56

To elucidate p53-dependency on combined treatment with radiation and hyperthermia, growth inhibition and apoptosis were analysed using transplantable human tumour. Human head and neck squamous cell carcinoma (HNSCC) cells carrying different p53 genes were transplanted into the thigh of nude mice. When the mean diameter of tumour reached 5-6 mm, the tumours were exposed to X-rays (2 Gy) or Carbon-ion (C-) beams (1 Gy) followed by heating at 42 degrees C for 20 min. Tumour growth inhibition was evaluated by measuring the diameters of tumour. The induction of apoptosis and accumulation of apoptosis-related proteins were also analysed by immunohistochemical staining. Synergistic enhancement of tumour growth inhibition by hyperthermia was observed in wild-type p53 tumours treated with X-rays or C-beams but not in mutant p53 tumours. The incidence of apoptotic cells and activated-caspase-3-positive cells after combined treatment with them were significantly high in wild-type p53 tumours compared with that in mutant p53 tumours. The hyperthermic enhancement of tumour growth inhibition by X-ray- or C-beam-irradiation was p53-dependent, suggesting that it might be highly correlated with p53-dependent apoptosis.
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PMID:p53-dependent hyperthermic enhancement of tumour growth inhibition by X-ray or carbon-ion beam irradiation. 1262 37

The chronological changes in intracellular Ca(2+)concentrations ([Ca(2+)](i)) were analysed during heat-induced apoptosis in human lung cancer cell lines LK-2 (squamous cell carcinoma) and LU65A (large cell carcinoma). In LK-2 cells, increased [Ca(2+)](i) levels were maintained at levels between 250-350 nm 9 h after heat-shock. Treatment with BAPTA, an intracellular Ca(2+) chelator, prior to heat-shock, decreased the frequency of heat-induced apoptosis in LK-2, while thapsigargin, a selective endoplasmic reticulum Ca(2+)-ATPase inhibitor, did not change the number of apoptotic cells, regardless of the presence or absence of Ca(2+)-supplemented medium. In LU65A cells, treatment with BAPTA or thapsigargin did not alter the apoptotic rates. Western blotting demonstrated that, although expression of Bax and Bcl-2 were not changed by heat-shock, p53 expression was elevated in LK-2, but not LU65A cells. Immunohistochemistry showed that p53 was localized predominantly in the cytoplasms of LK-2 cells, suggesting that p53 protein is not functional in LK-2. Heat-shock also elevated activities of caspase-3, -8 and -9 in both cell lines. It is concluded that a temporal increase in [Ca(2+)](i) is the important initiating factor in hyperthermia-induced apoptosis in LK-2 cells and that, in these two lung cancer cell lines, apoptosis may occur through 'cross-talk' between p53-independent mitochondrial and death receptor pathways.
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PMID:Elevated levels of intracellular Ca2+ and apoptosis in human lung cancer cells given heat-shock. 1262 40

Photodynamic therapy (PDT) can result in both types of cell death, apoptosis or necrosis. Several steps in the induction and execution of apoptosis depend on ATP and the intracellular ATP level has been shown to be one determinant in whether apoptosis or necrosis occurs. Therefore, photochemical damage of cellular targets involved in energy supply might play a crucial role in the mode of cell death being executed. The present study is aimed at the characterization of changes in cellular energy supply and the associated cell death modes in response to PDT. Using the human epidermoid carcinoma cell line A431 and aluminium(III) phthalocyanine tetrasulfonate chloride (2.5 microM) as a photosensitizer, we studied the changes in mitochondrial function and intracellular ATP level after irradiation with different light doses. Employing assays for caspase-3 activation and nuclear fragmentation, 50% of the cells were found to undergo apoptosis after irradiation between 2.5 to 3.5 J cm(-2) while the remainder died by necrosis. At higher light doses (> 6 J cm(-2)), neither caspase-3 activation nor nuclear fragmentation was observed and this suggests that these cells died exclusively by necrosis. Necrotic cell death was also associated with a rapid decline in mitochondrial activity and intracellular ATP. By contrast, with apoptosis the loss of mitochondrial function was delayed and the ATP level was maintained at near control levels for up to eight hours which was far beyond the onset of morphological changes. These data suggest that, depending on the light dose applied, both, necrosis as well as apoptosis can be induced with AlPcS4 mediated PDT and that photodamage in energy supplying cellular targets may influence the mode of cell death. Further, it is speculated that cells undergoing apoptosis in response to PDT might maintain a high ATP level long enough to complete the apoptotic program.
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PMID:Characterization of the cell death modes and the associated changes in cellular energy supply in response to AlPcS4-PDT. 1265 13

Interferon-gamma (IFN-gamma) induced cell death in five oral squamous cell carcinoma (SCC) lines. Cell death was specific to IFN-gamma treatment and did not occur with either IFN-alpha or TNF-alpha. IFN-gamma did not induce typical apoptotic phenotype in cells, such as morphological changes and DNA ladder formation. Caspase-3 was partially activated by IFN-gamma. Protein levels of molecular chaperones were examined in cells treated with IFN-gamma. Among these, levels of heat shock protein 27 (Hsp27) were specifically reduced upon IFN-gamma treatment of oral SCC cells. Recombinant clones overexpressing Hsp27 were more resistant to IFN-gamma-induced cell death than parent cells. Conversely, cells expressing a dominant-negative mutant of Hsp27, in which three serine residues (15, 78 and 82) were replaced by glycine, were hypersensitive to the effects of IFN-gamma and exhibited a typical apoptotic phenotype. Pretreatment of cells with IFN-gamma enhanced apoptotic cell death induced by cisplatin. Our data suggest that IFN-gamma suppresses Hsp27 expression in oral SCC cells and blocks the inhibitory effects of this molecular chaperone on apoptotic cell death. Moreover, IFN-gamma initiates the transition of oral SCC cells to the proapoptotic and/or aborted apoptotic state. Hsp27 plays a crucial role in the inhibition of apoptosis of oral SCC cells. Our findings highlight the importance of employing IFN-gamma in combination with certain anticancer drugs as treatments for oral cancer. We suggest that Hsp27 plays a significant role in the IFN-gamma-induced sensitization of oral SCC cells to anticancer drugs.
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PMID:Interferon-gamma downregulates Hsp27 expression and suppresses the negative regulation of cell death in oral squamous cell carcinoma lines. 1270 Jun 31

Retinoids that regulate cell growth, differentiation, and apoptosis have shown promising results in preclinical studies and in a few clinical trials of cancer chemoprevention and therapy. However, the clinical use of retinoids is limited by resistance of certain malignant cells to their antitumor effects and by side effects. To identify more potent retinoids, we examined the effects of heteroarotinoids (Hets), new synthetic retinoids with reduced toxicity, on the growth of human head and neck squamous cell carcinoma (HNSCC) lines. Six Hets with different retinoic acid receptor activation potentials were found to exhibit distinct efficacies. The most potent among the Hets examined, SHetA2, [[(4-nitrophenyl)amino][2,2,4,4-tetramethyl thiochroman-6-yl)amino] methane-1-thione], was more effective than either all-trans- or 9-cis-RA. The growth of UMSCC38, the most sensitive among the eight HNSCC cell lines examined, was suppressed by ShetA2 in a dose- and time-dependent fashion. SHetA2-induced apoptosis in UMSCC38 cells was comparable with N-(4-hydroxyphenyl)retinamide (4HPR). Reactive oxygen species (ROS) generation in the UMSCC38 cells was increased by SHetA2, and this effect was suppressed by the antioxidant butylated hydroxyanisol, which also suppressed SHetA2-induced apoptosis. SHetA2 suppressed mitochondrial permeability transition and enhanced cytochrome c release from mitochondria. Both of these effects were prevented by cyclosporin A, which also decreased SHetA2-induced apoptosis. SHetA2 increased caspase-3-like activity, and a caspase-3 inhibitor diminished SHetA2-induced apoptosis. Several retinoid receptor antagonists failed to prevent apoptosis induction by SHetA2. These results demonstrate that SHetA2 is a potent, receptor-independent, apoptosis inducer that acts on the mitochondria in HNSCC cells. Further investigation of the potential of SHetA2 in prevention and therapy of HNSCC is warranted also because of much lower toxicities compared with receptor active retinoids.
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PMID:The synthetic heteroarotinoid SHetA2 induces apoptosis in squamous carcinoma cells through a receptor-independent and mitochondria-dependent pathway. 1283 80

Mutations in the p53 tumor suppressor gene have recently been reported to have an impact on clinical trials of several human tumors, including head and neck cancers. To confirm the p53-dependence of X-ray induced apoptosis, we used two cell lines derived from a human squamous cell carcinoma (SAS) with identical genetic backgrounds, except for the p53 gene, which are SAS/mp53 cells with mp53 and SAS/neo cells with wtp53. We previously reported that the radiosensitivity, Caspase-3 activity and apoptosis frequency in SAS/neo cells were clearly high as compared with SAS/mp53 cells. In order to elucidate the expression of apoptosis-related genes after irradiation, we used cDNA array analysis. The expressions of apoptosis-inductive genes, such as DFF40, Caspase-3, Caspase-8, Caspase-9, Caspase-10 and CRADD, were increased by X-ray irradiation in SAS cells with wtp53, but not in SAS cells expressing mp53. These results suggest that the X-ray sensitivity of wtp53 cells may come from the expression of these apoptosis-related genes.
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PMID:Analysis of apoptosis-related gene expression after X-ray irradiation in human tongue squamous cell carcinoma cells harboring wild-type or mutated p53 gene. 1284 98

Our study was conducted to investigate whether anticancer drugs, cisplatin (CDDP) and/or 5-fluorouracil (5-FU), can modulate Fas-mediated apoptosis in oral squamous cell carcinoma (OSCC) cell lines. When OSCC cell lines, NA and HSC-4, were treated with CDDP and/or 5-FU, Fas and its mRNA expression on the plasma membrane were enhanced. An increase in caspase-3 and -8 activities was then observed by the addition of agonistic anti-Fas antibody, CH-11. Apoptosis of OSCC cells treated with anticancer drugs were significantly enhanced by CH-11, whereas untreated cells were nearly resistant to apoptosis. Moreover, the combination of CDDP and 5-FU resulted in an increasing susceptibility to apoptosis. Caspase-3 and -8 inhibitors, but not caspase-9 inhibitor, reduced Fas-mediated apoptosis enhanced by the anticancer drugs. Furthermore, OSCC cells treated with anticancer drugs exhibited decreased cellular FADD-like interleukin 1-converting enzyme-inhibitory protein (c-FLIP) levels, whereas neither the Fas-associated death domain-containing protein (FADD) nor procaspase-8 changed the expression. Moreover, antisense oligonucleotide to c-FLIP confirmed that down-regulation of c-FLIP induced sensitization to Fas-mediated apoptosis. These results suggest that CDDP and 5-FU may enhance the susceptibility to Fas-mediated apoptosis through down-regulation of c-FLIP. From these findings, a new potential strategy may be developed to improve the efficacy of anticancer drugs.
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PMID:Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS-mediated apoptosis by cisplatin and 5-fluorouracil. 1284 62


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