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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthetic flavonoid flavone acetic acid (FAA) has anti-tumor activity against a variety of transplanted tumors in mice through mechanisms which likely involve effects on tumor vasculature and the host immune system. The aims of the present in vitro study were to compare the sensitivity of tumor and endothelial cells to FAA treatment and to assess if nitric oxide and superoxide are involved in the FAA-mediated suppression of cell proliferation. FAA at 1 mM concentration was approximately two times more effective in suppressing proliferation of endothelial than tumor cells. The anti-proliferative effect of 1 mM FAA on endothelial cells was partially blocked by inhibitors to various superoxide-producing enzymes (xanthine oxidase, cyclooxygenase, poly-ADP-ribose polymerase, ribonucleotide reductase) and completely inhibited by the direct scavengers of superoxide lucigenin and Tiron. In contrast, inhibitors of nitric oxide were unable to prevent the effects of FAA on proliferation. FAA induced apoptosis of endothelial cells, which was not affected by inhibitors of nitric oxide or superoxide. Our data imply that FAA inhibits proliferation of endothelial cells by a superoxide-dependent mechanism and induces apoptosis by a nitric oxide and superoxide-independent mechanism.
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PMID:Oxidative stress contributes to the anti-proliferative effects of flavone acetic acid on endothelial cells. 1095 82

Ribonucleotide reductase (RR) is the rate-limiting enzyme for the de novo synthesis of deoxyribonucleotides. Its activity is significantly increased in tumor cells related to the proliferation rate. Therefore, the enzyme is considered to be an excellent target for cancer chemotherapy. In the present study, we investigated whether the antineoplastic effects of trimidox (3,4, 5-trihydroxybenzamidoxime), a novel inhibitor of RR, were due to induction of apoptosis.HL-60 cells were incubated with various concentrations of trimidox. Consequently, cell morphology, DNA condensation, annexin binding, DNA fragmentation, and signature type cleavage of poly(ADP-ribose)polymerase and gelsolin were determined. We also tested the involvement of CD95 and CD95 ligand in apoptosis induction. Furthermore, we examined the c-myc expression of HL-60 cells after incubation with trimidox in order to elucidate a possible association between c-myc expression and induction of apoptosis in the case of trimidox. Trimidox incubation caused a time-dependent increase of c-myc RNA expression and this was accompanied by the induction of apoptosis. Apoptosis was triggered independently of CD95 by the activation of caspases and PARP cleavage. We conclude that trimidox is able to induce programmed cell death. The induction of apoptosis was demonstrated by various biochemical and morphological methods and seems to be associated with the induction of c-myc. Apoptosis was induced by the activation of caspases and without change of the CD95 and CD95 ligand expression.
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PMID:Trimidox, an inhibitor of ribonucleotide reductase, induces apoptosis and activates caspases in HL-60 promyelocytic leukemia cells. 1098 93

The flavonoid baicalin (baicalein 7-D-beta-glucuronate), isolated from the dried root of Scutellaria baicalensis Georgi (Huang Qin), is widely used in the traditional Chinese herbal medicine for its anti-inflammatory, anti-pyretic and anti-hypersensitivity effects. In the present study, we investigated the in vitro effects of baicalin on the growth, viability, and induction of apoptosis in several human prostate cancer cell lines, including DU145, PC-3, LNCaP and CA-HPV-10. The cell viability after treating with baicalin for 2-4 days was quantified by a colorimetric 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-s ulfophenyl)- 2H-tetrazolium (MTS) assay. The results showed that baicalin could inhibit the proliferation of prostate cancer cells. The responses to baicalin were different among different cell lines, with DU145 cells being the most sensitive and LNCaP cells the most resistant. Baicalin caused a 50% inhibition of DU145 cells at concentrations of 150 microM or above. The inhibition of proliferation of prostate cancer cells after a short period of exposure to baicalin was associated with induction by apoptosis, as evidenced by the typical nuclear fragmentation using Hoechst 33258 staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) labeling, DNA fragmentation, activation of caspase-3 and cleavage of poly-ADP-ribose polymerase (PARP). The results indicate that baicalin has direct anti-tumor effects on human prostate cancer cells.
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PMID:Induction of apoptosis in prostate cancer cell lines by a flavonoid, baicalin. 1105 52

Epidemiological studies have suggested that the consumption of fruits and vegetables that provide several classes of compounds, including Indole-3-carbinol (I3C), may have chemopreventive activity against breast cancer. Several in vitro and in vivo animal studies also provide convincing evidence for the anti-tumor activity of I3C, however, the molecular mechanism(s) by which I3C exerts its biological effects on breast cancer cells has not been fully elucidated. In this study, we investigated the effects of I3C in Her-2/neu over-expressing MDA-MB-435 breast cancer cells and compared these results with parental cells transfected with control vector. We focused our investigation in elucidating the molecular mechanism(s) by which I3C induces apoptosis in breast cancer cells. Our data show that I3C inhibits breast cancer cell growth in a dose dependent manner in Her-2/neu over-expressing and in normal Her-2/neu expressing cells. Induction of apoptosis was also observed in these cell lines when treated with I3C, as measured by poly (ADPribose) polymerase (PARP) and caspase-3 activation. In addition, we found that I3C up-regulates Bax, down-regulates Bcl-2 and, thereby, increased the ratio of Bax to Bcl-2 favoring apoptosis. These results suggest that the alteration in the expression of these genes may play an important role in mediating the biological effects of I3C. Moreover, we also show the cellular localization of Bax by confocal microscopy, which showed diffuse distribution of Bax throughout the cytoplasmic compartment in breast cancer cells in control culture. However, in I3C treated cells, Bax showed a punctate pattern of distribution that was localized in the mitochondria. From these results, we conclude that the over-expression and translocation of Bax to mitochondria causes mitochondrial depolarization and activation of caspases, which may be one of the mechanism(s) by which I3C induces apoptotic processes in I3C treated breast cancer cells. Overall, our present data provide a novel molecular mechanism(s) by which I3C elicits its biological effects on both Her-2/neu over-expressing and with normal Her-2/neu expressing breast cancer cells, suggesting that I3C could be an effective agent in inducing apoptosis in breast cancer cells.
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PMID:Translocation of Bax to mitochondria induces apoptotic cell death in indole-3-carbinol (I3C) treated breast cancer cells. 1112 63

Anchorage-independent growth is a hallmark of tumor cells. We compared gene expression profiles of anchored and nonanchored human mammary carcinoma cells to study this phenomenon. In this study, we show that anchorage had striking effects on cell growth and morphology but altered transcript levels from a limited number of genes. Only about 1% of mRNA transcripts detected in these cells was altered by anchorage. These include genes related to amino acid and polyamine metabolism, apoptosis, ion channels, cytoskeletal and stress proteins, transcription factors, and growth factors. Some of these may be crucial for the survival of transformed cells. For example, clusterin and the tumor necrosis factor-related apoptosis inducing ligand (TRAIL) were suppressed by anchorage, which could help prevent programmed cell death of these tumor cells. In addition to suppressing TRAIL expression, anchorage also decreased the susceptibility of these tumor cells to TRAIL-induced apoptosis as determined by poly(ADP-ribose) phosphorylase cleavage, annexin-V binding (P < 0.01), and cell cycle analysis (P < 0.0001). These data may help explain mechanisms by which anchorage prevents apoptosis of cells that would otherwise experience anoikis. Thus, genes found to be altered by this analysis could serve as potential targets for anticancer therapy. These findings suggest that TRAIL may be used as a means to target circulating epithelial tumor cells before their attachment and colonization at new sites.
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PMID:Global effects of anchorage on gene expression during mammary carcinoma cell growth reveal role of tumor necrosis factor-related apoptosis-inducing ligand in anoikis. 1124 30

By serological screening of a breast tumor cDNA library we have identified a novel human gene, tnkl, encoding an ankyrin-related protein with a high degree of similarity to tankyrase, the poly(ADP-ribose)polymerase associated with human telomeres (Smith et al, Science 282: 1484). The tnkl gene maps to chromosome 10, while the tnks gene encoding tankyrase is located on chromosome 8. The predicted 1166-aa protein product of the tnkl gene is 78% identical to human tankyrase and 62% to a putative D. melanogaster protein. Since the proteins have essentially identical domain structures, the corresponding genes form a distinct gene family. The possible link between TNKL and cancer justifies its further functional analysis.
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PMID:Cloning and characterization of TNKL, a member of tankyrase gene family. 1129 70

The synthetic retinoid, N-(4-hydroxyphenyl)retinamide (4HPR), which is currently being evaluated in clinical trials for cancer prevention and therapy, inhibits the growth of a variety of malignant cells through induction of apoptosis. However, in the majority of tumor cells, this inhibitory effect of 4HPR requires high concentrations (>1 microM), which exceed the peak plasma level measured in humans. In the present study, we compared and contrasted the effects of several synthetic retinamides on the growth of human lung and head and neck cancer cells in vitro. We found that some retinamides, especially N-(2-carboxyphenyl)retinamide (2CPR), exhibited better growth inhibitory effects than 4HPR in some of the cell lines. 2CPR exerted potent growth inhibitory effects in 5 of 10 head and neck cancer cell lines and in 1 of 10 lung cancer cell lines (IC(50), <0.8 microM). 2CPR (1 microM) induced apoptosis ranging from 10 to 60% in four of five cell lines, whereas 4HPR was ineffective at the same concentration. Unlike 4HPR, 2CPR (up to 10 microM) failed to induce reactive oxygen species production in these sensitive cell lines but could activate caspases 3 and 7 as well as increase poly(ADP-ribose)polymerase cleavage. Interestingly, the effect of 2CPR on cell growth could be suppressed by the specific retinoic acid receptor pan antagonist AGN193109. Our results suggest that 2CPR acts via retinoic acid receptors and may be a good candidate for prevention and treatment of some head and neck and lung cancers.
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PMID:Identification of retinamides that are more potent than N-(4-hydroxyphenyl)retinamide in inhibiting growth and inducing apoptosis of human head and neck and lung cancer cells. 1140 8

Non-steroidal anti-inflammatory drugs (NSAIDs) can induce tumor cells to undergo apoptosis in vitro. They have also shown cancer-preventive activity in vivo. The mechanism of their effects is, however, not well defined. We investigated the mechanism by which a new NSAID, NS398, induces apoptosis in esophageal cancer cell lines. NS398 decreased cell viability in 2 cyclo-oxygenase-2-positive (COX-2(+)) esophageal cancer cell lines but not in a COX-2(-) cell line. DNA fragmentation and TUNEL assays demonstrated that NS398 induced the 2 COX-2(+) cancer cell lines to undergo apoptosis. The percentage of apoptosis induced by NS398 was associated with the level of COX-2 expression. Further investigation showed that the cytochrome c pathway was responsible for NS398-induced apoptosis; i.e., cytochrome c was released from mitochondria, caspase-9 and caspase-3 were activated and finally poly(ADP-ribose)polymerase (PARP) was cleaved. Furthermore, the effect of NS398 was inhibited by the caspase inhibitor Z-DEVD-FMK and prostaglandin E(2). In contrast, bcl-2, bax, c-myc, Fas and Fas-ligand showed minor changes. Altogether, our data suggest that induction of apoptosis by NS398 is associated with COX-2 expression and occurs through the cytochrome c-dependent pathway, which sequentially activates caspase-9 and caspase-3 and cleaves PARP.
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PMID:Induction of apoptosis by cyclo-oxygenase-2 inhibitor NS398 through a cytochrome C-dependent pathway in esophageal cancer cells. 1141 Aug 69

Gallic acid (GA) derivatives, 3,4-methylenedioxyphenyl 3,4,5-trihydroxybenzoate (GD-1) and S-(3,4-methylenedioxyphenyl)3,4,5-trihydroxythiobenzoate (GD-3), were previously reported to induce apoptosis in tumor cells with IC50s of 14.5 microm and 3.9 microm, respectively. To elucidate the mechanism by which these gallic acid derivatives (GDs) induce apoptosis, we studied whether GD-1 and GD-3 can activate caspases. When promyelocytic leukemia HL-60RG cells were treated with GD-1 and GD-3, poly(ADP-ribose)polymerase (PARP), a substrate of caspase-3, was cleaved into 85 kDa of degradative product with increasing incubation time. GA also activated PARP cleavage, which was inhibited by catalase, N-acetyl-L-cysteine (NAC), and intracellular Ca2+ chelator 1,2-bis(2-aminophenoxyethane)-N,N,N,N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), in addition to a caspase inhibitor, Z-VAD-FMK. Its inhibitory pattern was identical with that of hypoxanthine/xanthine oxidase. On the other hand, GD-1- and GD3-induced PARP cleavage was not suppressed by catalase or NAC, but by BAPTA-AM. This suggested that the GD-elicited signaling pathway is different from GA's. Taken together, GDs activated caspase-3 following intracellular Ca2+ elevation independent of reactive oxygen species. Thus, it became evident that the signaling pathway leading to apoptosis was regulated by GDs in a different manner from GA.
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PMID:Ca2+-Dependent caspase activation by gallic acid derivatives. 1145 29

The tumor-suppressor p53 undergoes extensive poly(ADP-ribosyl)ation early during apoptosis in human osteosarcoma cells, and degradation of poly(ADP-ribose) (PAR) attached to p53 coincides with poly(ADP-ribose)polymerase-1, (PARP-1) cleavage, and expression of p53 target genes. The mechanism by which poly(ADP-ribosyl)ation may regulate p53 function has now been investigated. Purified wild-type PARP-1 catalyzed the poly(ADP-ribosyl) of full-length p53 in vitro. In gel supershift assays, poly(ADP-ribosyl)ation suppressed p53 binding to its DNA consensus sequence; however, when p53 remained unmodified in the presence of inactive mutant PARP-1, it retained sequence-specific DNA binding activity. Poly(ADP-ribosyl)ation of p53 by PARP-1 during early apoptosis in osteosarcoma cells also inhibited p53 interaction with its DNA consensus sequence; thus, poly(ADP-ribosyl)ation may represent a novel means for regulating transcriptional activation by p53 in vivo.
Neoplasia
PMID:Poly(ADP-ribosyl)ation of p53 in vitro and in vivo modulates binding to its DNA consensus sequence. 1149 11


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