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)

Full length Mcl-1 is an anti-apoptotic protein consisting of two closely migrating 42/40kDa species. We now investigated the relationship of these isoforms to the expression of cell cycle stimulatory (cyclin A) and inhibitory (p21WAF1) proteins and to the induction of apoptosis in wt p53 MCF-7 and mutant p53 SKBR3 human breast carcinomas. The latter cells exhibited lower 42kDa Mcl-1, higher expression of cyclin A relative to that of p21WAF1, and apoptosis in response to okadaic acid, a phosphatase 1/2A inhibitor. The proteasome inhibitor MG-115 selectively increased expression of the 40kDa Mcl-1 isoform and induced p21WAF1, but also promoted preferential apoptosis in SKBR3 cells. Neither okadaic acid nor MG-115 caused comparable effects in MCF-7 cells. However, vanadate or acetyl furanonaphthoquinone induced the 40kDa Mcl-1 and greater Jun kinase (JNK) phosphorylation without apoptosis-associated PARP fragmentation in MCF-7 cells. Our data suggest that the higher susceptibility of SKBR3 cells to undergo apoptosis may be partly due to their greater proliferative potential (cyclin A), low expression of the anti-apoptotic 42kDa Mcl-1 isoform, and suboptimal JNK activation in response to stress.
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PMID:Relationship of Mcl-1 isoforms, ratio p21WAF1/cyclin A, and Jun kinase phosphorylation to apoptosis in human breast carcinomas. 1235 45

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including vasodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelia (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties. Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis by upregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53, poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understanding at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease.
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PMID:The role of nitric oxide in cancer. 1252 89

One of the cellular responses to DNA damaging events is the activation of programmed cell death, also known as apoptosis. Apoptosis is an important process in limiting tumorigenesis by eliminating cells with damaged DNA. This view is reinforced by the finding that many genes with pro-apoptotic function are absent or altered in cancer cells. The tumor suppressor p53 performs a significant role in apoptotic signaling by controlling expression of a host of genes that have pro-apoptotic or pro-survival function. The S(N)1 DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) triggers apoptosis and the upregulation/phosphorylation of p53; however, the mechanism(s) governing MNNG-induced cell death remain unresolved. We observed that the human lymphoblastoid cell line WTK-1, which expresses mutant p53, shows far less sensitivity to the cytotoxic effects of MNNG than the closely related, p53-normal line TK-6. Exposure to 15 muM MNNG (LD50 at 24 h in TK-6) leads to a kinetically slower rate of apoptotic onset in WTK-1 cells compared to TK-6 as judged by viability assays and approaches that directly examine apoptotic onset. Similar results were obtained using an unrelated human lymphoblastoid line B310 expressing reduced levels of p53 due to E6 oncoprotein expression, indicating that MNNG activates both p53-dependent and -independent apoptotic mechanisms and that these two mechanisms are discernable by the rates which they trigger apoptotic onset. We document, during time points corresponding to peak apoptotic response in TK6, WTK-1, B310, and B310-E6, that these cell lines show marked decreases in mitochondrial transmembrane potential and increases in cytochrome c within the cytosolic fraction of MNNG-treated cells. Consistent with these events, we observed that both caspase-9 and -3 are activated in our panel of lymphoblastoid cells after MNNG exposure. We also found, using both broad spectrum and specific inhibitors, that blocking caspase activity in TK-6 and B310 cells had a significant effect on apoptotic advance, but that this treatment had no effect on entry of WTK-1 or B310-E6 cells into apoptosis. Finally, the PARP inhibitors benzamide and 6(5H)-phenanthridinone exerted notable inhibition of PARP activity and the nuclear translocation of the mitochondrial protein AIF (apoptosis-inducing factor) in MNNG-treated cells; however, these compounds exhibited no detectable inhibitory effects on MNNG-induced death in human lymphoblastoid cells. These observations suggest that PARP activity is not required during MNNG-triggered apoptosis in this cell type. Taken together, our observations support the conclusion that MNNG activates multiple apoptogenic pathways that contain both common and unique mechanisms.
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PMID:The monofunctional alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine triggers apoptosis through p53-dependent and -independent pathways. 1558 79

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that NCTD also induces apoptosis in human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant) as evidenced by nuclear condensation, TUNEL labeling, DNA fragmentation and cleavage of PARP. Apoptosis induced by NCTD was both dose- and time-dependent. We found NCTD did not induce Fas and FasL, implying that it activated other apoptosis pathways. Our data showed that NCTD caused accumulation of cytosolic cytochrome c and activation of caspase-9, suggesting that apoptosis occurred via the mitochondria mediated pathway. NCTD enhanced the expression of Bax in SAS cells consistent with their p53 status. Moreover, we showed that NCTD downregulated the expression of Bcl-2 in Ca9-22 and Bcl-XL in SAS. Our results suggest that NCTD-induced apoptosis in oral cancer cells may be mediated by an increase in the ratios of proapoptotic to antiapoptotic proteins. Since oral cancer cells with mutant p53 or elevated Bcl-XL levels showed resistance to multiple chemotherapeutic agents, NCTD may overcome the chemoresistance of these cells and provide potential new avenues for treatment.
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PMID:Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. 1559 95

Neuroblastoma is a pediatric tumor accounting for 15% of childhood cancer deaths and has a poor prognosis in children >1 year of age. We investigated the ability of apigenin, a nonmutagenic dietary flavonoid that has been shown to have antitumor effects in various tumor cell lines, to inhibit growth and induce apoptosis of the human neuroblastoma cell lines NUB-7, LAN-5, and SK-N-BE(2). Apigenin inhibited colony-forming ability and survival, and induced apoptosis of NUB-7 and LAN-5 cells. The presence of the C2-C3 double bond and the 4'-OH group on the flavonoid structure correlated with the growth-inhibitory potential of apigenin. Furthermore, apigenin inhibited NUB-7 xenograft tumor growth in anonobese diabetic/severe combined immunodeficiency mouse model, likely by inducing apoptosis. Apigenin did not inhibit survival of primary sympathetic neurons, suggesting that it is not toxic to nontransformed cells. The mechanism of action of apigenin seems to involve p53, as it increased the levels of p53 and the p53-induced gene products p21WAF1/CIP1 and Bax. Furthermore, apigenin (15-60 micromol/L) induced cell death and apoptosis of neuroblastoma cells expressing wild-type but not mutant p53. Apigenin increased caspase-3 activity and PARP cleavage, and Z-VAD-FMK, a broad-spectrum caspase-3 inhibitor, rescued NUB-7 cells from apigenin-mediated apoptosis indicating that apigenin induced apoptosis in acaspase-dependent manner. Overexpression of Bcl-X(L) rescued NUB-7 from apigenin-induced cell death, suggesting that Bax activity is important for the action of apigenin. Apigenin is thus a candidate therapeutic for neuroblastoma that likely acts by regulating a p53-Bax-caspase-3 apoptotic pathway.
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PMID:Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuroblastoma. 1565 48

2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) has been used to treat patients with advanced solid tumours. However, the molecular mechanisms are not well understood. In the present study, we report that SarCNU inhibited proliferation of human HK-1 and CNE-2 nasopharyngeal carcinoma (NPC) in vivo and in vitro. In vitro study showed that wild-type p53 HK-1 cells were 3-fold more sensitive to SarCNU than p53 mutant CNE-2 cells. G2/M arrest, reduction in p21(Cip1/Waf1) and inactivation of cellular cdc-2 activity were seen in both SarCNU-treated HK-1 and CNE-2 cells. Upregulation of p53, phosphorylated p53 at Ser15 and biochemical markers for apoptosis, such as cleaved caspase-3, cleaved caspase-7 and cleaved PARP, were observed in SarCNU-treated HK-1 but not CNE-2 cells. The levels of cyclin B1, Wee1 and phosphorylated cdc-2 but not total cdc-2 in HK-1 cells were significantly reduced by SarCNU treatment. In contrast to HK-1 cells, decrease in total cdc-2 but increase in phosphorylated cdc-2 at Tyr15, cyclin B1 and Wee1 was observed in CNE-2 cells treated with SarCNU. Introduction of mutant p53 into HK-1 cells resulted in growth enhancement in vivo and increased resistance to SarCNU-induced apoptosis in vitro. Furthermore, CNE-2 cells transfected with wild-type p53 became susceptible to SarCNU-induced apoptosis in vitro but not their growth rate in vivo. The data indicate that in NPC cells SarCNU-induced apoptosis was p53-dependent while SarCNU-induced G2/M arrest was mediated by altering the levels of cyclin B1-cdc-2 complex and phosphorylation of cdc-2 at Tyr15 resulting in inactivation of cellular cdc-2 activity. Our data suggest a potential use of SarCNU in the treatment of NPC.
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PMID:2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) exhibits p53-dependent and -independent antiproliferative activity in human nasopharyngeal carcinoma cells in vitro and in vivo. 1614 32

MEK1/2 inhibitors like U0126 can potentiate or antagonize the antitumor activity of cytotoxic agents such as cisplatin, paclitaxel or vinblastine, depending on the drug or the target cells. We now investigated whether U0126, differentially regulates melanoma signaling in response to UV radiation or betulinic acid, a drug lethal against melanoma. This report shows that U0126 inhibits early response (ERK) kinase activation and cyclin A expression in wt p53 C8161 melanoma exposed to either UV radiation or betulinic acid. However, U0126 does not protect from UV damage, but counteracts betulinic acid-mediated apoptosis in the same cells. Protection from the latter drug by joint treatment with U0126 was also evident in wt p53 MelJuso melanoma and mutant p53 WM164 melanoma. The latter cells were the most responsive to betulinic acid, showing a selective decline in the cdk4 protein, without a comparable change in other key cell cycle proteins like cdc2, cdk2, cdk7 or cyclin A, prior to apoptosis-associated PARP fragmentation. Laser scanning cytometry also showed that betulinic acid induced a significant increase in chromatin condensation in WM164 melanoma irrespective of whether they were in adherent form or as multicellular spheroids. All these betulinic acid-induced changes were counteracted by U0126. Our data show for the first time that (a) cdk4 protein is an early target of betulinic acid-induced apoptosis and (b) unrestricted ERK signaling favours betulinic acid-induced apoptosis, but this is counteracted by U0126, partly through counteracting chromatin condensation and restoring Akt activation decreased by betulinic acid treatment.
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PMID:Signalling responses linked to betulinic acid-induced apoptosis are antagonized by MEK inhibitor U0126 in adherent or 3D spheroid melanoma irrespective of p53 status. 1615 20

The role of clusterin/apolipoprotein J (Clu/ApoJ) and Bcl-2 on C(2)-ceramide-induced apoptosis of embryonic human diploid fibroblasts, MRC-5 and immortalized adult skin keratinocytes, HaCaT was investigated. C(2)-ceramide-induced apoptosis of HaCaT in a time- and dose-dependent manner, while in MRC-5 only at higher concentrations. There was a dose-dependent accumulation of Clu/ApoJ and downregulation of Bcl-2 which correlated with C(2)-ceramide-induced apoptosis of MRC-5. While overexpression of Bcl-2 suppressed C(2)-ceramide-mediated apoptosis in both cell types, Clu/ApoJ failed to do so, accessed by morphological changes, DNA fragmentation and PARP cleavage. There was no change in the expression of endogenous p53 or p21(Waf1/Cip1) upon C(2)-ceramide treatment of MRC-5. However, mutant p53(143ala) increased the sensitivity of MRC-5 to C(2)-ceramide-induced apoptosis by markedly downregulating Bcl-2, pointing to a role for p53. These results suggested that whereas downregulation of Bcl-2 may be a crucial factor involved in C(2)-ceramide-induced apoptosis, accumulation of Clu/ApoJ may be a signal of stress response. Moreover, the ceramide-activated apoptotic pathway may be regulated by p53.
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PMID:Bcl-2 but not clusterin/apolipoprotein J protected human diploid fibroblasts and immortalized keratinocytes from ceramide-induced apoptosis: role of p53 in the ceramide response. 1629 52

Since diethyl dithiocarbamate (DEDTC) forms complexes with either zinc or copper, and 8-hydroxyquinoline (8-OHQ) also complexes with copper, we now compared the cytotoxic activity of Cu[DEDTC]2, Zn[DEDTC]2 and Cu[8-OHQ]2. This report shows that at nanomolar levels, only copper-[DEDTC]2, suppresses proliferation and clonogenicity of SKBR3 human breast carcinoma, concurrently with induction of apoptosis-associated PARP fragmentation. Susceptibility to these agents was paralleled by reactive oxygen generation (ROS) and greater expression of anti-oxidant enzymes like MnSOD and catalase, with no comparable effect on Cu/Zn superoxide dismutase. The lethal effects of Cu[DEDTC]2 manifested when adding the two separate aqueous components or the preformed synthetic complexes in DMSO, was prevented by N-acetyl cysteine or glutathione, with no comparable protection afforded by non-thiol anti-oxidants like mannitol or DMSO. Exogenously added catalase also protected cells from Cu[DEDTC]2, suggesting that this complex may kill after the levels of superoxide anion [O2*-] dismutated by MnSOD increase hydrogen peroxide-related stress. Cu[DEDTC]2 also induced p21WAF1, a cdk inhibitor usually not inducible in mutant p53 tumors like SKBR3 carcinoma, correlating with dephosphorylation of the Sp1 transcription factor. Concentrations of Cu[DEDTC]2 cytotoxic for SKBR3 carcinoma did not induce comparable damage versus normal diploid human WI-38 fibroblasts. In contrast to the cytotoxic effect of nM levels of Cu[DEDTC]2 against SKBRR3 cells, no response was seen in the same cells exposed to 20 microM cis-platin. Since neither DEDTC bound to zinc, nor copper bound to 8-OHQ showed comparable cytotoxicity, our results suggest that the greater activity of copper-DEDTC reflects a specific structure-activity relationship for the active complex. Since Cu[DEDTC]2 shows more effectiveness than other metal-chelator complexes, it may be worth further investigation as an alternative to cancer therapies.
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PMID:Suppression of survival in human SKBR3 breast carcinoma in response to metal-chelator complexes is preferential for copper-dithiocarbamate. 1641 83

Until recently, the use of Se-methylselenocysteine (MSC) as selective modulator of the antitumor activity and selectivity of anticancer drugs including irinotecan, a topoisomerase I poison, had not been evaluated. Therapeutic synergy between MSC and irinotecan was demonstrated by our laboratory in mice bearing human squamous cell carcinoma of the head and neck tumors. In FaDu xenografts, a poorly differentiated tumor-expressing mutant p53, the cure rate was increased from 30% with irinotecan alone to 100% with the combination of irinotecan and MSC. Cellular exposure to cytotoxic concentration of SN-38, the active metabolite of irinotecan (0.1 microM) alone and in combination with noncytotoxic concentration of MSC (10 microM) did not result in additional enhancement of chk2 phosphorylation and downregulation of specific DNA replication-associated proteins, cdc6, MCM2, cdc25A, nor increase in PARP cleavage, caspase activation and the 30-300 kb DNA fragmentation induced by SN-38 treatment. MSC did not alter significantly markers associated with apoptosis, nor potentiate irinotecan-induced apoptosis. These results indicate that apoptosis is unlikely to be one of the main mechanism associated with the observed in vivo therapeutic synergy. In contrast, significant downregulation of cyclooxygenase-2 (COX-2) expression and activity was observed in the cells exposed to SN-38 in combination with MSC compared to SN-38 alone. Moreover, the inhibition of PGE(2) production was also observed in the cells treated with the combination as compared with SN-38 alone. Analysis of tumor tissues at 24 h after treatment with synergistic modality of irinotecan and MSC revealed significant downregulation of COX-2, inducible nitric oxide synthase (iNOS) and hypoxia-induced factor-1alpha expression (HIF 1alpha). Moreover, decreased microvessel density was observed after irinotecan treatment with the addition of MSC. These results suggest that observed therapeutic synergy correlates with the inhibition of neoangiogenesis through the downregulation of COX-2, iNOS and HIF-1alpha expression.
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PMID:Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1alpha expression, resulting in reduced angiogenesis. 1651 18


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