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: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of human prostate carcinoma PC-3 cells were investigated. Whereas CDCA and UDCA had no effects on the growth of cells in a concentration range we have tested, HS-1199 and HS-1200 completely inhibited the cell proliferation, and HS-1183 showed a weak inhibitory activity. This proliferation-inhibitory effect of the synthetic bile acid derivatives was due to the induction of apoptosis, which was confirmed by observing DNA fragmentation, chromatin condensation and cleavage of PARP. Flow cytometric analysis also revealed that the synthetic bile acid derivatives arrested the cell cycle progression at the G1 phase, which effects were associated with inhibition of phosphorylation of pRB and enhanced binding of pRB and E2F-1. They also suppressed Cdk2 and cyclin E-dependent kinase activities without changes of their expressions. Furthermore, the synthetic bile acids increased the levels of Cdk inhibitor, p21WAF1/CIP1, expression and activated the reporter construct of p21WAF1/CIP1 promoter in p53-independent manner, and p21WAF1/CIP1 proteins induced by the synthetic bile acid derivatives were associated with Cdk2 and proliferating cell nuclear antigen. These distinctive features suggest that it is possible to create the new drugs useful for cancer therapy from the synthetic bile acid derivatives as lead compounds.
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PMID:Apoptosis and modulation of cell cycle control by synthetic derivatives of ursodeoxycholic acid and chenodeoxycholic acid in human prostate cancer cells. 1296 88

Sulforaphane (SFN), a constituent of cruciferous vegetables, is highly effective in affording protection against chemically induced cancers in animal models. Here, we report that SFN inhibited proliferation of cultured PC-3 human prostate cancer cells by inducing apoptosis that was characterized by appearance of cells with sub-G0/G1 DNA content, formation of cytoplasmic histone associated DNA fragments and cleavage of poly(ADP-ribose)polymerase (PARP). SFN-induced apoptosis was associated with up-regulation of Bax, down-regulation of Bcl-2 and activation of caspases-3, -9 and -8. SFN-induced apoptosis, and cleavage of procaspase-3 and PARP were blocked upon pre-treatment of cells with pan caspase inhibitor z-VADfmk, and specific inhibitors of caspase-9 (z-LEHDfmk) and caspase-8 (z-IETDfmk) suggesting involvement of both caspase-9 and caspase-8 pathways in SFN-induced cell death. Oral administration of SFN (5.6 micro mol, 3 times/week) significantly inhibited growth of PC-3 xenografts in nude mice. For instance, 10 days after starting therapy, the average tumor volumes in control and SFN-treated mice were 170 +/- 13 and 80 +/- 14 mm3, respectively, reflecting a >50% reduction in tumor volume due to SFN administration. To the best of our knowledge, the present study is the first published report to document in vivo anticancer activity of SFN in a tumor xenograft model.
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PMID:Sulforaphane induces caspase-mediated apoptosis in cultured PC-3 human prostate cancer cells and retards growth of PC-3 xenografts in vivo. 1451 58

Taxotere is a cytotoxin effective in treating breast and prostate cancer. It stabilizes microtubules and causes catastrophic cell cycle arrest in G2/M. Taxanes also initiate apoptosis by activating signal pathways, such as the jun N-terminal kinase (JNK) pathway. Strategies aimed at potentiating cell death signaling may improve their efficacy while lessening the potential side effects. We reported that all-trans retinoic acid (ATRA) potentiated taxane-mediated cell death. Here we investigated whether ATRA potentiates cell death signaling through the JNK pathway. Activation of JNK by Taxotere 0.01, 0.1 and 1.0 microM was observed at 24 h in adherent cells and increased at 48 h. Taxotere 0.001 microM-induced JNK activation started after 48 h and increased at 72 h. The timing and intensity of PARP cleavage was similar to that of JNK activation. JNK activation and PARP cleavage induced by 30 nM Taxotere at 48 h were reversed by curcumin, PD169316 and SP600125, JNK inhibitors in order of progressive specificity. None of these inhibitors had an effect on p38 or ERK phosphorylation. All three inhibitors reversed Taxotere-induced phosphorylation of Bcl-2. ATRA induced JNK activation at 24, 48 and 72 h. Incubating cells with ATRA 0.01 microM for 3 days prior to Taxotere treatment potentiated Taxotere-induced JNK activation 24 and 48 h later, an effect sustained for 72 h. Cytotoxicities from 3-day ATRA 0.01 microM incubations were synergistic with subsequent 1-h Taxotere 0.01, 0.1 and 1.0 microM incubations in breast cancer cell lines MCF-7 and MDA-MB-231 and in prostate cancer cell lines LNCaP and PC-3, and additive in breast cancer cell line SK-Br-3. These data demonstrate the potentiation of Taxotere-induced cell death by ATRA pretreatment in breast and prostate cancer cells, and support a mechanism through accentuated and sustained JNK activation.
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PMID:All-trans retinoic acid potentiates Taxotere-induced cell death mediated by Jun N-terminal kinase in breast cancer cells. 1472 71

alpha-Tocopherol and its synthetic derivative, a-tocopheryl succinate (alpha-TS), are known to inhibit proliferation of cancer cells. alpha-TS is considered a more desirable anticancer agent because of the ability to induce apoptosis. It has been established previously that the whole intact alpha-TS molecule is necessary for its pro-apoptotic activity. For this reason, alpha-TS is not suitable for oral use because the ester bond linking succinate to tocopherol is subject to hydrolysis by intestinal esterases. One approach to overcome this problem is to replace the ester bond with an ether bond, since the latter is resistant to esterase-mediated hydrolysis. alpha-Tocopheryloxybutyrate (alpha-TOB) is the ether analog of alpha-TS. In this study, we compared the potency of alpha-TS and alpha-TOB using a panel of bioassays: cell growth, TUNEL labelling for apoptosis, PARP cleavage, caspase-3 and caspase-9 activation, as well as Akt and JNK phosphorylation. The experiments were carried out in two human prostate cancer cell lines: LNCaP and PC-3. Our results showed that alpha-TOB was capable of inhibiting cell growth and inducing apoptosis, although alpha-TOB was less active than alpha-TS on an equimolar basis. In general, it took twice as much alpha-TOB as alpha-TS to achieve the same response. Nonetheless, these two compounds shared the same mechanism of targeting the Akt and JNK signaling pathways, and activating the intrinsic cell death mediators of caspase-9 and caspase-3. Cellular analysis of alpha-TS and alpha-TOB showed that alpha-TOB was taken up as efficiently as alpha-TS (if not more so), suggesting that the lower activity of alpha-TOB is an inherent property of the molecule and not due to impaired uptake. Additional evidence is provided to show that beta-TS may act at the membrane level to interfere with Akt phosphorylation, although the exact nature of this disruption remains unclear. The future design of new anticancer tocopherol analogs should incorporate the ether linkage of the side chain for esterase resistance as well as other structural modifications for enhanced blocking of membrane signaling.
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PMID:Cellular and molecular effects of alpha-tocopheryloxybutyrate: lessons for the design of vitamin E analog for cancer prevention. 1573 14

Neoxanthin and fucoxanthin, which have the characteristic structure of 5,6-monoepoxide and an allenic bond, were previously found to reduce the viability of human prostate cancer cells most intensively among 15 dietary carotenoids tested. In the present study, the induction of apoptosis in PC-3 cells by these two carotenoids was characterized by morphological changes, DNA fragmentation, an increased percentage of hypodiploid cells, and cleavages of caspase-3 and PARP. The ratio of apoptotic cells reached more than 30% after treatment for 48 h with 20 microM carotenoids. They reduced the expression of Bax and Bcl-2 proteins, but not Bcl-X(L). Fucoxanthin accumulated in the cells at the same level as neoxanthin. Moreover, fucoxanthinol, a deacetylated product of fucoxanthin, formed in the cells treated with fucoxanthin and reached a level comparable to that of fucoxanthin after incubation for 24 h. Treatment by fucoxanthinol alone also induced apoptosis in PC-3 cells. Thus, neoxanthin and fucoxanthin treatments were found to induce apoptosis through caspase-3 activation in PC-3 human prostate cancer cells.
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PMID:Neoxanthin and fucoxanthin induce apoptosis in PC-3 human prostate cancer cells. 1573 90

Overexpression of the helix-loop-helix protein Id-1 has been reported in over 20 types of cancer. While a number of factors have been demonstrated to regulate Id-1 gene transcription, little is known about the mechanisms responsible for its degradation. In this study, we have demonstrated that Id-1 protein stability was regulated by TNFalpha in prostate cancer cells. We found that exposure of prostate cancer cell lines, DU145 and PC-3, to TNFalpha resulted in a rapid and significant downregulation of the Id-1 protein level. The fact that neither the Id-1 promoter activity nor the Id-1 mRNA level was affected by the TNFalpha treatment suggested that the decrease in Id-1 protein was not due to the suppression of gene transcription. In addition, the half-life of the Id-1 protein was decreased in both cell lines in the presence of TNFalpha, and the addition of an ubiquitin/proteasome inhibitor (MG-132) prior to the TNFalpha treatment completely blocked the effect of the TNFalpha-induced Id-1 protein degradation. Furthermore, introduction of a Flag-tag sequence into the N-terminus region of the Id-1 protein, which has been shown to stabilize the protein, was able to protect the Id-1 protein from TNFalpha-induced degradation. These results suggest that TNFalpha downregulated Id-1 through activation of the ubiquitin/proteasome degradation pathway in prostate cancer cells. Interestingly, in both DU145 and PC-3 cells, the decrease of Id-1 protein was associated with the activation of apoptotic pathway, as evidenced by the increased expression of cleaved PARP and caspase 3. In addition, TNFalpha failed to downregulate Id-1 in a sub-line of LNCaP cells that was resistant to TNFalpha-induced apoptosis. These results further suggest that the downregulation of Id-1 may facilitate TNFalpha-induced apoptosis in prostate cancer cells. In conclusion, our findings indicate that Id-1 protein may be regulated by TNFalpha through the ubiquitin/proteasome degradation pathway and the stability of the Id-1 protein appears to correlate with the sensitivity of TNFalpha-induced apoptosis.
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PMID:Proteasome mediated degradation of Id-1 is associated with TNFalpha-induced apoptosis in prostate cancer cells. 1612 20

This study investigated the anticancer activity and related mechanisms of neolignans, especially threo, erythro-manassantin A (compound 2), which are isolated from Saururus chinensis, in PC-3 cells. Compound 2 strongly inhibited the proliferation of PC-3 cells in a dose-dependent manner. Different cell morphologies were observed depending on the concentration of compound 2, which suggested different growth inhibitory mechanisms. DNA flow cytometry indicated that both low and high concentrations of compound 2 induced the arrest of PC-3 cells in G1 phase. Western blot analyses showed that hyperphosphorylated Rb and E2F-1 were decreased, whereas hypophosphorylated Rb was increased. The cells treated with compound 2 at 200 ng/ml showed shrinkage morphologically, and the staining of annexin V-FITC revealed apoptotic cell death of these cells. The induction of apoptosis was accompanied by the cleavage of caspase-3, -8, and -9, as well as the downregulation of the Bcl-2 and the upregulation of Bax. By contrast, at low compound 2 concentration (1 ng/ml), the cells arrested in G1 showed characteristic changes in morphology, such as an enlarged, flattened cell shape; the majority strongly expressed SA-beta-galactosidase activity. The number of cells undergoing apoptosis was negligible, and no poly(ADP-ribose) polymerase (PARP) cleavage was observed. The increase of p21 was noticed. However, it appeared to be transient rather than sustained. The protein p27 may be important for maintaining the senescence machinery induced by compound 2 because p27 expression was increased at low concentration compared with that at high concentration. In conclusion, compound 2 showed a significant growth inhibitory effect in PC-3 cells via two different mechanisms, i.e., apoptosis at high concentration and senescence at low concentration.
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PMID:Neolignans from Saururus chinensis inhibit PC-3 prostate cancer cell growth via apoptosis and senescence-like mechanisms. 1614 81

The 52-aminoacid peptide adrenomedullin (AM) is expressed in the normal and malignant prostate. We have previously shown that prostate cancer cells produce and secrete AM, which acts as an autocrine growth inhibitory factor. We have evaluated in the present study the role of AM in prostate cancer cell apoptosis, induced either by serum deprivation or treatment with the chemotherapeutic agent etoposide (which acts as an inhibitor of topoisomerase II). For this purpose we over-expressed AM in PC-3, DU 145 and LNCaP cells, which were transfected with an expression vector carrying AM. We also treated the parental cell lines with synthetic AM in normal culture conditions and in conditions of induced-apoptosis. After serum removal, AM prevented apoptosis in DU 145 and PC-3 cells, but not in LNCaP cells. When treated with etoposide, AM prevented apoptosis in PC-3 and LNCaP cells, but not in DU 145 cells. Cell cycle analysis demonstrated a significant decrease in the percentage of AM-overexpressing PC-3 cells in the subG0/G1 phase after treatment with etoposide, as compared to the percentage of mock-transfected PC-3 treated cells. Western blot showed that protein levels of phosphorylated ERK1/2 increased in parental PC-3 cells after treatment with etoposide. In PC-3 cells overexpressing AM, phosphorylated ERK1/2 basal levels were lower than basal levels of parental PC-3 cells, and treatment with etoposide did not result in such an increase. Etoposide produced a significant increase in cleaved PARP in parental PC-3 cells. However, PC-3 clones overexpressing AM that were treated with etoposide only showed a mild increase in fragmented PARP. The ratio Bcl-2/Bax was reduced in parental or mock-transfected PC-3 cells after treatment with etoposide. On the contrary, this ratio was not reduced in PC-3 clones with AM overexpression that were treated with etoposide. All these data demonstrate that AM plays a protective role against induced apoptosis in prostate cancer cells. These results may have important implications in prostate cancer resistance to chemotherapeutic agents.
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PMID:Adrenomedullin prevents apoptosis in prostate cancer cells. 1629 90

Clusterin (CLU), whose role is still debated, is differentially regulated in several patho-physiological processes and invariably induced during apoptosis. In heat shock response, CLU is considered a stress-inducible, pro-survival/cyto-protective factor via an HSE element present in his promoter. In both human prostate PNT1A and PC-3 epithelial cells we found that apoptotic stimuli induced nuclear localization of CLU (nCLU), and that overexpression of nCLU is pro-apoptotic. We show here that CLU time-course accumulation kinetic is different from that of HSP70 in these cells, thus other factor(s) might mediate HSF-1 activation and CLU expression. Sub-lethal heat shock inhibited the secretion of CLU (sCLU), leading to increased cytoplasm accumulation of CLU (cCLU) in association to cell survival. At difference, lethal heat stress caused massive accumulation of pro-apoptotic nCLU in cells dying by caspase-3-dependent apoptosis. Double heat stress (sub-lethal heat shock followed by recovery and lethal stress) induced HSP70 and thermo-tolerance in PNT1A cells, but not in PC-3 cells. In PNT1A cells, CLU secretion was inhibited and cCLU was accumulated, suggesting that cCLU might be pro-survival, while in PC-3 cells accumulation of nCLU was concomitant to caspase-3 induction and PARP activation instead. Thus, CLU expression/sub-cellular localization is strictly related to cell fate. In particular, nCLU and physiological levels of HSP70 affected cell survival in an antagonistic fashion. Prevalence of heat-induced nCLU, not allowing PC-3 cells to cope with heat shock, could be the rational explaining why malignant cells are more sensitive to heat when delivered by minimally invasive procedures for ablation of localized prostate cancer.
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PMID:Nuclear clusterin accumulation during heat shock response: implications for cell survival and thermo-tolerance induction in immortalized and prostate cancer cells. 1633 65

Rigorous and systematic pre-clinical studies are necessary and essential to establish the efficacy and safety of Oriental herbs and formulas in order to transform traditional herbal practices into evidence-based medicine. Here we evaluated the anti-cancer activities of the ethanol extract of Ka-mi-kae-kyuk-tang (KMKKT), a formula of ten Oriental herbs, with a battery of in vitro and in vivo mechanism-based biomarkers involving angiogenesis, apoptosis and metastasis. The results show that KMKKT suppressed the vascular endothelial responses by inhibiting basic fibroblast growth factor (bFGF)-induced ERK1/2 phosphorylation, cell migration as well as tube formation in the human umbilical vein endothelial cell model, and decreased the hypoxia-induced HIF1alpha and vascular epithelial growth factor (VEGF) expression in the mouse Lewis lung carcinoma (LLC) cells in vitro, and inhibited the bFGF-induced angiogenesis in chick chorioallantoic membrane model, and in the Matrigel plugs in mice. Intraperitoneal delivery of KMKKT potently inhibited the growth of the subcutaneously inoculated LLC cells in syngenic mice. In addition, KMKKT inhibited the invasion ability of the mouse colon 26-L5 cancer cells in vitro and decreased their formation of liver metastasis when intraportally inoculated in syngenic mice. Furthermore, KMKKT suppressed the growth of the human PC-3 prostate cancer xenografts in athymic nude mice and averted the cancer-related body weight loss. The in vivo cancer growth suppression was associated with a decreased microvessel density and VEGF abundance as well as an increased PARP cleavage and the TUNEL-positive apoptosis. Together, our data support broad-spectra in vivo anti-cancer activities of KMKKT targeting angiogenesis, apoptosis and metastasis without any adverse effect on the body weight. This formula merits serious consideration for further evaluation for the chemoprevention and treatment of cancers of multiple organ sites.
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PMID:An oriental herbal cocktail, ka-mi-kae-kyuk-tang, exerts anti-cancer activities by targeting angiogenesis, apoptosis and metastasis. 1677 83


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