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)

The flavanone naringenin (Nar), especially abundant in the Mediterranean diet, is reported to have anti-proliferative effects in many cancer cell lines. Antioxidant activities, kinase and glucose uptake inhibition have been proposed as molecular mechanisms for these effects. In addition, an anti-estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity could play a role in the Nar anti-tumoral effects. Here, we tested the ability of Nar to activate a specific, rapid signal transduction pathway committed to the generation of an apoptotic cascade in the presence of one of the two estrogen receptor (ER) isoforms (i.e., ERalpha or ERbeta). Cancer cells containing transfected (human cervix epitheloid carcinoma HeLa cells) or endogenous ERalpha (human hepatoma HepG2 cells) or ERbeta (human colon adenocarcinoma DLD-1 cells) were used. Our results show that Nar exerts an anti-proliferative effect only in the presence of ERalpha or ERbeta. Moreover, Nar stimulation induces the activation of p38/MAPK leading to the pro-apoptotic caspase-3 activation and to the poly(ADP-ribose) polymerase cleavage in all cancer cell lines considered. Notably, Nar shows an anti-estrogenic effect only in ERalpha containing cells; whereas in ERbeta containing cells, Nar mimics the 17beta-estradiol effects. These findings indicate new steps in the mechanism underlying ER-dependent anti-proliferative effects of Nar suggesting new potential chemopreventive actions of flavonoids on cancer growth.
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PMID:Mechanisms of naringenin-induced apoptotic cascade in cancer cells: involvement of estrogen receptor alpha and beta signalling. 1554 29

Allyl sulfides are characteristic flavor components obtained from garlic. These sulfides are thought to be responsible for their epidemiologically proven anticancer effect on garlic eaters. This study was aimed at clarifying the molecular basis of this anticancer effect of garlic by using human colon cancer cell lines HCT-15 and DLD-1. The growth of the cells was significantly suppressed by diallyl trisulfide (DATS, HCT-15 IC50 = 11.5 microM, DLD-1 IC50 = 13.3 microM); however, neither diallyl monosulfide nor diallyl disulfide showed such an effect. The proportion of HCT-15 and that of DLD-1 cells residing at the G1 and S phases were decreased by DATS, and their populations at the G2/M phase were markedly increased for up to 12 h. The cells with a sub-G1 DNA content were increased thereafter. Caspase-3 activity was also dramatically increased by DATS. Fluorescence-activated cell sorter analysis performed on the cells arrested at the G1/S boundary revealed cell cycle-dependent induction of apoptosis through the transition of the G2/M phase to the G1 phase by DATS. DATS inhibited tubulin polymerization in an in vitro cell-free system. DATS disrupted microtubule network formation of the cells, and microtubule fragments could be seen at the interphase. Peptide mass mapping by liquid chromatography-tandem mass spectrometry analysis for DATS-treated tubulin demonstrated that there was a specific oxidative modification of cysteine residues Cys-12beta and Cys-354beta to form S-allylmercaptocysteine with a peptide mass increase of 72.1 Da. The potent antitumor activity of DATS was also demonstrated in nude mice bearing HCT-15 xenografts. This is the first paper describing intracellular target molecules directly modified by garlic components.
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PMID:Diallyl trisulfide suppresses the proliferation and induces apoptosis of human colon cancer cells through oxidative modification of beta-tubulin. 1621 63

Sea cucumber is a health-beneficial food, and contains a variety of physiologically active substances including glycosphingolipids. We show here the sphingoid base composition of cerebrosides prepared from sea cucumber and the cytotoxicity against human colon cancer cell lines. The composition of sphingoid bases prepared from sea cucumber was different from that of mammals, and the major constituents estimated from mass spectra had a branched C17-19 alkyl chain with 1-3 double bonds. The viability of DLD-1, WiDr and Caco-2 cells treated with sea cucumber sphingoid bases was reduced in a dose-dependent manner and was similar to that of cells treated with sphingosine. The sphingoid bases induced such a morphological change as condensed chromatin fragments and increased the caspase-3 activity, indicating that the sphingoid bases reduced the cell viability by causing apoptosis in these cells. Sphingolipids of sea cucumber might therefore serve as bioactive dietary components to suppress colon cancer.
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PMID:Isolation of sphingoid bases of sea cucumber cerebrosides and their cytotoxicity against human colon cancer cells. 1715 82

Sweetpotato leaves (Ipomoea batatas L.) contain a high content of polyphenolics that consist of caffeic acid, chlorogenic acid, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, and 3,4,5-tri-O-caffeoylquinic acid. We investigated the suppression of the proliferation of selected human cancer cells by phenolic compounds isolated from sweetpotato leaf. The human cancer cells used in this research included a stomach cancer (Kato III), a colon cancer (DLD-1), and a promyelocytic leukemia cell (HL-60). Caffeic acid and di- and tricaffeoylquinic acids dose-dependently depressed cancer cell proliferation, and the difference in sensitivity between caffeoylquinic acid derivatives and each kind of cancer cell was observed. Specifically, 3,4,5-tri-O-caffeoylquinic acid effectively depressed the growth of three kinds of cancer cells, and caffeic acid had an exceptionally higher effect against HL-60 cells than other di- and tricaffeoylquinic acids. In attempting to clarify the mechanism of growth suppression with the addition of the apoptotic inhibitor N-ethylmaleimide, we observed that the nuclear granulation in 3,4,5-tri-O-caffeoylquinic acid-treated HL-60 cells suggested apoptosis induction. This effect was confirmed by DNA fragmentation, an increase of caspase-3 activity, and expression of c-Jun. Growth suppression of HL-60 cells by 3,4,5-tri-O-caffeoylquinic acid was determined to be the result of apoptotic death of the cells. These results indicate that 3,4,5-tri-O-caffeoylquinic acid may have potential for cancer prevention.
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PMID:Growth suppression of human cancer cells by polyphenolics from sweetpotato (Ipomoea batatas L.) leaves. 1719 31

To identify cancer-specific targets, we have conducted a synthetic lethal screen using a small interfering RNA (siRNA) library targeting approximately 4,000 individual genes for enhanced killing in the DLD-1 colon carcinoma cell line that expresses an activated copy of the K-Ras oncogene. We found that siRNAs targeting baculoviral inhibitor of apoptosis repeat-containing 5 (survivin) significantly reduced the survival of activated K-Ras-transformed cells compared with its normal isogenic counterpart in which the mutant K-Ras gene had been disrupted (DKS-8). In addition, survivin siRNA induced a transient G(2)-M arrest and marked polyploidy that was associated with increased caspase-3 activation in the activated K-Ras cells. These results indicate that tumors expressing the activated K-Ras oncogene may be particularly sensitive to inhibitors of the survivin protein.
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PMID:Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells. 1723 86

The cellular functions regulated by 17beta-estradiol (E2) start after the hormone binds to its receptors (i.e., ERalpha and ERbeta). These act as ligand-dependent transcription factor transactivating target genes. In addition, E2 induces non-genomic actions, whose activation is triggered by a fraction of the ERs localized at the plasma membrane. Palmitoylation allows ERalpha to localize at the plasma membrane, to associate with caveolin-1, and, upon E2 stimulation, to activate rapid signals relevant for cell proliferation. The existence of a mechanism, which allows ERbeta localization at the plasma membrane and its putative role in anti-proliferative E2 effects is completely unknown. Here, the susceptibility of ERbeta to undergo palmitoylation and the role played by this process has been analyzed in DLD-1 containing endogenous ERbeta or in HeLa cells transiently transfected with ERbeta or ERalpha expression vectors. As for ERalpha, palmitoylation is necessary for ERbeta localization at the plasma membrane and its association with caveolin-1 but, in contrast to ERalpha, the E2 binding increases ERbeta association with caveolin-1 and the p38 member of MAPK family. Moreover, the palmitoyl acyl transferase (PAT) inhibitor blocks the ability of ERbeta-E2 complex to activate p38 impairing the receptor-dependent activation of downstream proapoptotic cascade (i.e., caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage). Consequently, palmitoylation must be considered to be a molecular device for ERbeta, which allows these receptors to interact with the plasma membrane and to regulate E2-induced non-genomic functions relevant to the anti-proliferative effect of this hormone.
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PMID:Role of ERbeta palmitoylation in the inhibition of human colon cancer cell proliferation. 1739 84

Alk(en)yl sulfides are characteristic flavor components of garlic. Several lines of epidemiological study indicate that the risk of a certain cancer can be prevented by consumption of garlic. In this manuscript, we examined the anticancer property of garlic-derived alk(en)yl sulfides, and the molecular basis especially for diallyl trisulfide which is a major constituent of the garlic oil. Alk(en)yl sulfides with different numbers of sulfur atom (i.e., mono-, di-, and trisulfide) were synthesized and purified (>99%). The anticancer activity of the alk(en)yl sulfides was primarily examined using human colon cancer cells HCT-15 and DLD-1. The growth of the cells was significantly suppressed by diallyl trisulfide, but neither diallyl monosulfide nor diallyl disulfide showed such an effect. The number of cells arrested at G2/M phase, the cells with a sub-G1 DNA content, and the cells with caspase-3 activity were dramatically increased by diallyl trisulfide treatment. Diallyl trisulfide disrupted microtubule network formation of the cells, and microtubule fragments could be seen at the interphase. There was a specific oxidative modification of cysteine residues Cys12 beta and Cys354 beta, forming S-allylmercaptocysteines in the tubulin molecule. These results suggest that diallyl trisulfide is responsible, at least in part, for the epidemiologically proven anticancer effect for garlic eaters.
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PMID:Anticancer effects of diallyl trisulfide derived from garlic. 1829 48

Caspase-3 is responsible for the cleavage of several proteins including the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Designed on the cleavage site of PARP, Ac-Asp-Glu-Val-Asp-H has been reported as a highly specific inhibitor. To overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of tetra-peptidyl aldehydes, di- and tri-peptidyl caspase-3 inhibitors have been synthesized. Here, the synthesis and the inhibition properties of peptidyl aldehydes Z-tLeu-Asp-H, Z-tLeu-Val-Asp-H, and Z-Val-tLeu-Asp-H are reported. Z-tLeu-Asp-H, Z-tLeu-Val-Asp-H, and Z-Val-tLeu-Asp-H inhibit competitively human caspase-3 activity in vitro with K(i)(0)=3.6nM, 18.2nM, and 109nM, respectively (pH 7.4 and 25 degrees C). Moreover, Z-tLeu-Asp-H impairs apoptosis in human DLD-1 colon adenocarcinoma cells without affecting caspase-8. Therefore, Ac-Asp-Glu-Val-Asp-H can be truncated to Z-tLeu-Asp-H retaining nanomolar inhibitory activity in vitro and displaying action in whole cells, these properties reflect the unprecedented introduction of the bulky and lipophilic tLeu residue at the P(2) position.
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PMID:Human caspase-3 inhibition by Z-tLeu-Asp-H: tLeu(P2) counterbalances Asp(P4) and Glu(P3) specific inhibitor truncation. 1885 75

Polyunsaturated fatty acids (PUFAs) exhibit beneficial biological functions in carcinogenic processes. We examined the effects of PUFAs in the acid and phospholipid forms on three colon cancer cell lines (HT-29, Caco-2, and DLD-1). Docosahexaenoic acid (DHA) and eicosapentaenoic (EPA) in both acid and phospholipid forms showed growth inhibition effects on experimental colon cancer cell lines. But these PUFAs had the strongest growth-inhibitory effect on HT-29 than Caco-2 and DLD-1. Combined application of PUFAs and sodium butyrate (NaBt) increased the growth inhibition. Growth inhibition was apparently caused by increased lipid peroxidation. DHA or EPA in combination with NaBt significantly increased caspase-3 activity compared to control. DHA and DHA-rich phosphatidylcholine decreased Bcl-2 level in HT-29 and Caco-2 cells.
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PMID:Growth inhibition and induction of apoptosis of colon cancer cell lines by applying marine phospholipid. 1911 82

Currently 5-fluorouracil (5-FU) plays a central role in the chemotherapeutic regimens for colorectal cancers and thus it is important to understand the mechanisms that determine 5-FU sensitivity. The expression profiles of human colon cancer cell line DLD-1, its 5-FU-resistant subclone DLD-1/FU and a further 21 types of colon cancer cell lines were compared to identify the novel genes defining the sensitivity to 5-FU and to estimate which population of genes is responsible for 5-FU sensitivity. In the hierarchical clustering, DLD-1 and DLD-1/FU were most closely clustered despite over 100 times difference in their 50% inhibitory concentration of 5-FU. In DLD-1/FU, the population of genes differentially expressed compared to DLD-1 was limited to 3.3%, although it ranged from 4.8% to 24.0% in the other 21 cell lines, thus indicating that the difference of 5-FU sensitivity was defined by a limited number of genes. Next, the role of the cellular inhibitor of apoptosis 2 (cIAP2) gene, which was up-regulated in DLD-1/FU, was investigated for 5-FU resistance using RNA interference. The down-regulation of cIAP2 efficiently enhanced 5-FU sensitivity, the activation of caspase 3/7 and apoptosis under exposure to 5-FU. The immunohistochemistry of cIAP2 in cancer and corresponding normal tissues from colorectal cancer patients in stage III revealed that cIAP2 was more frequently expressed in cancer tissues than in normal tissues, and cIAP2-positive patients had a trend toward early recurrence after fluorouracil-based chemotherapy. Although the association between drug sensitivity and the IAP family in colorectal cancer has not yet been discussed, cIAP2 may therefore play an important role as a target therapy in colorectal cancer.
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PMID:Down-regulation of cIAP2 enhances 5-FU sensitivity through the apoptotic pathway in human colon cancer cells. 1930 91


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