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 wide variation in sensitivity of cancer cells to TRAIL- or histone deacetylase (HDAC) inhibitor - induced apoptosis precludes successful treatment of cancer with these agents. We report here that TRAIL and SBHA synergistically induce apoptosis of melanoma cells as revealed by quantitative analysis using the normalized isobologram method. This is supported by enhanced activation of caspase-3 and cleavage of its substrates, PARP and ICAD. Co-treatment with SBHA and TRAIL did not enhance formation of the death-inducing signaling complex (DISC) and processing of caspase-8 and Bid, but potentiated activation of Bax and release of Cytochrome C and Smac/DIABLO from mitochondria into the cytosol. SBHA down-regulated Bcl-X(L), Mcl-1 and XIAP, but up-regulated Bax, Bak, and the BH3-only protein Bim(EL). Up-regulation of the latter by SBHA was attenuated by the presence of TRAIL, which was inhibitable by the pan-caspase inhibitor z-VAD-fmk. Inhibition of Bim by siRNA attenuated conformational changes of Bax, mitochondrial apoptotic events, and activation of caspase-3, leading to marked inhibition of the synergy between SBHA and TRAIL. Thus, Bim plays an essential role in synergistic induction of apoptosis by SBHA and TRAIL in melanoma.
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PMID:Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. 1705 34

Malignant melanoma is particularly resistant to conventional chemotherapy and radiotherapy. For this reason in the past years a huge variety of new compounds has been developed with potential chemotherapeutic activity which needs to be tested in vitro and in vivo. We investigated the in vitro action of three new experimental antifolate substances (MR7, MR21 and MR36) with a critical target for thymidylate synthase (TS), an essential enzyme for DNA synthesis. The response of two melanoma cell lines (SK-MEL-2 derived from malignant melanoma metastasis and SK-MEL-28 derived from primary malignant melanoma) was examined after treatment with these substances. The antifolate agents induced apoptosis in SK-MEL-2 and SK-MEL-28 cells as confirmed by the TUNEL technique and Comet Assay. Western-blot analysis showed a down-regulation of Bcl-2 protein level and PARP cleavage, otherwise p53 and Bax expressions were not modulated. Moreover, these antifolate-induced apoptosis was accompanied by both pro-caspase-9 and -8 activations. These results were supported by the use of the pan-caspases inhibitor Z-VAD-FMK that almost completely decreased the amount of apoptosis in both the melanoma cell lines treated with antifolate. In conclusion our results show that TS inhibitors are able to induce apoptosis through a caspase-mediated pathway, but without the involvement of the p53/Bax signalling.
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PMID:New thymidylate synthase inhibitors induce apoptosis in melanoma cell lines. 1711 21

Apoptotic deficiency is one of the mechanisms leading to chemoresistance due to the potential of many chemotherapeutic drugs to induce apoptosis. We have examined drug-induced apoptosis in the chemosensitive human melanoma cell line MeWo, as well as in its resistant sublines, which were selected by continuous exposure to etoposide (MeWo(Eto1)) and cisplatin (MeWo(Cis1)). In former studies, activation of the mitochondrial pro-apoptotic pathway could not be demonstrated in etoposide-resistant cells after exposure to etoposide. A significant reduction of PARP [poly (ADP-ribose) polymerase] cleavage and caspase activation, but unimpaired DNA fragmentation, was seen in cisplatin-resistant cells after treatment with cisplatin. In the current study, we investigated effects of chemotherapeutic drugs different from the selecting agents cisplatin and etoposide on the observed modulations of the mitochondrial apoptotic pathway. We analysed dose-dependent release of cytochrome c, caspase-9 activation, cleavage of PARP and activation of effector caspases in etoposide and cisplatin-resistant cells after exposure to etoposide, teniposide, cisplatin or fotemustine. In analogy to etoposide exposure, we could not demonstrate any activation of the apoptotic pathway in etoposide-resistant cells after exposure to teniposide, another topoisomerase-II inhibitor. In contrast, exposure to cisplatin and fotemustine led to apoptotic cell death in these cells. This suggests that the deficiency of apoptosis in etoposide-resistant cells is dependent on the trigger by topoisomerase-II inhibitors. Analysis of cisplatin-resistant cells after etoposide and fotemustine exposure revealed an increased activity of the apoptotic pathway when compared with cisplatin exposure at corresponding survival rates in these cells. These results suggest that the observed modulations of the apoptotic pathway in resistant melanoma cell lines are specific for an anti-neoplastic drug and are not fixed at the molecular level, as different chemotherapeutic drugs are capable of overcoming these alterations.
Melanoma Res 2006 Dec
PMID:The altered apoptotic pathways in cisplatin and etoposide-resistant melanoma cells are drug specific. 1711 54

Indole-3-acetic acid (IAA) activation by horseradish peroxidase (HRP) has been suggested as a new cancer therapy. Interestingly, we found that ultraviolet B UVB radiation also can activate IAA and produce free radicals in a dose-dependent manner. In this study, we attempted to identify the free radicals generated by UVB-irradiated IAA (IAAUVB), and to determine whether IAAUVB can induce the apoptosis of G361 human melanoma cells. Since IAA/HRP produces reactive oxygen species (ROS), we examined whether IAAUVB-generated radicals include ROS. Our results show that IAAUVB-induced free radical production is not inhibited by catalase, superoxide dismutase, or sodium formate, indicating that ROS are not generated by IAAUVB. On the other hand, IAAUVB caused lipid peroxidation, and this was blocked by Trolox, a water-soluble vitamin E derivative. Moreover, we found that IAAUVB caused apoptotic cell death and that this was inhibited by a low temperature. We further investigated IAAUVB-mediated apoptotic pathways, and found that IAAUVB causes caspase-8, Bid, caspase-3 activation, and poly (ADP-ribose) polymerase (PARP) cleavage. In addition, these apoptotic pathways were also blocked by low temperature. From these results, we propose that IAAUVB-induced free radicals cause human melanoma cell apoptosis via a death receptor-mediated apoptotic pathway.
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PMID:Light-activated indole-3-acetic acid induces apoptosis in g361 human melanoma cells. 1714 72

Interactions between tumor cells and their substratum influence cancer progression by modulating cell proliferation and survival. We now investigated whether signaling responses to UV irradiation differ on adhesion-permissive or restrictive substrates. The latter conditions diminished spreading and proliferation of neo 6.3/C8161 melanoma in which metastasis is suppressed by introduction of neo-tagged chromosome 6, but permitted proliferation of human metastatic C8161 melanoma. Apoptosis-associated PARP cleavage and DNA fragmentation induced by UV irradiation were diminished on the restrictive substrate in C8161 melanoma. Genotoxic responses to UV irradiation like persistent increases in the phosphorylation of histone H2AX, induction of the tumor suppressor p53 protein and greater binding of this protein to its DNA consensus sequence, were all decreased on the restrictive substrate. The latter also promoted a 2 fold increase of DNA condensation in chromatin and enhanced activation of the survival - and invasion-associated MMP-9 gelatinase B, preferentially in metastatic C81261 melanoma. Our data suggest that adaptation to restrictive substrates in metastatic C8161 melanoma decreases UV-induced apoptosis, partly through attenuation of DNA damage signaling responses and changes in genomic organization.
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PMID:Attenuation of genotoxicity under adhesion-restrictive conditions through modulation of p53, gamma H2AX and nuclear DNA organization. 1720 47

In this work we tried to estimate the role of mitochondria in the ability of cells of two: melanotic and amelanotic transplantable melanoma lines to undergo spontaneous and camptothecin-induced apoptosis. We measured mitochondrial transmembrane potential (DeltaPsi) changes during culture without (spontaneous apoptosis) and with camptothecin (induced apoptosis) by using JC-1 staining and flow cytometry analysis. Cytochrome c release and PARP cleavage as the biological effects of DeltaPsim changes belonging to the phenomena observed during apoptosis were estimated by Western blotting. The results of our investigations showed in both transplantable melanoma cells the features indicating apoptosis: DeltaPsi changes, cytochrome c release and PARP cleavage, but the degree of observed changes depended on the phenotype of melanoma cells examined. After camptothecin treatment the changes were more pronounced in the amelanotic melanoma cells- the more aggressive line.
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PMID:Mitochondrial transmembrane potential in spontaneous and camptothecin-induced apoptosis of melanotic and amelanotic melanoma cells. 1720 90

Malignant melanoma is one of the most common cancer types among the Caucasian population. While the prognosis is excellent for patients diagnosed at an early stage and treated by adequate surgery, unresectable or advanced metastatic diseases shrink the overall survival at 5 years dramatically to less than 10%. For disseminated malignant melanoma, the appropriate systemic medical treatment is still controversial. Fortunately, progress in the molecular biology and in the understanding of pathogenesis has been made recently and should in the near future translate into molecular-based therapeutic strategies. In this review, we briefly describe the status of current treatment strategies and existing standards for malignant melanoma. We will focus on the new and emerging compounds including recent developments of targeted therapy such as antiangiogenic and immunomodulatory drugs, Bcl-2 antisense therapy, raf kinase inhibitors, heat shock protein modulators, anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 monoclonal antibody and finally PARP and proteasome inhibitors.
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PMID:Novel treatment strategies for malignant melanoma: a new beginning? 1720 6

Loss of pigment in hamster amelanotic melanoma line is accompanied by a faster growth rate, higher tumorigenicity and shorter animal survival time. Thus, the malignancy of melanoma increases during the alteration of melanotic (Ma) into amelanotic (Ab) line. As changes in the ability to undergo a spontaneous or induced apoptosis, and the role of caspases in this process during melanoma progression are not well defined, they were investigated in this work. Our results show that the proportion of spontaneously early apoptotic (caspase+/PI-) cells in the Ab line decreased in comparison to the Ma line. Cytochrome c release into cytosol, and the activation of effector caspases, estimated by PARP degradation clearly showed that during the spontaneous death in the cells from both melanoma lines intrinsic way of apoptosis was activated. Confocal and cytometric flow analyses indicate that camptothecin (CPT) induced apoptosis with caspase activation by the intrinsic way only in the amelanotic melanoma cells, even though cells of the Ma line also underwent CPT-induced apoptosis (the content of TUNEL-positive cells increased). Thus, our results suggest that melanoma progression, associated with a decreased ability to undergo spontaneous apoptosis but an increased susceptibility to CPT-induced apoptosis, relates to different levels of caspase activation; they also show that intrinsic way of apoptotis depends on the phenotype of melanoma cells, being more pronounced in the melanotic melanoma cells. On the other hand, melanotic melanoma cells resistance to camptothecin-induced apoptosis suggests that the melanogenic apparatus or melanin itself may have the protective effect on the ability of the melanoma cells to undergo apoptosis.
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PMID:The activity of caspases in spontaneous and camptothecin-induced death of melanotic and amelanotic melanoma cell. 1731 83

Melanoma is a highly metastatic cancer resistant to current chemotherapeutic and radiotherapeutic approaches. Several studies have shown that interactions between cancer cells and the extracellular matrix (ECM) are critical for the survival and invasion of metastatic cancer cells. In this study, we examine the effects of methylselenol generated from selenomethionine (SeMet) by methioninase (METase) on cell proliferation, adhesion, and expression of integrins in murine melanoma B16F10 cells, which are metastatic in the lungs of syngeneic C57BL/6J mice. Combined treatment with SeMet-METase decreased the expression of integrins alpha(4), beta(1), alpha(nu), and beta(3), and inhibited melanoma-ECM adhesion. Caspase-mediated apoptosis was induced following loss of cell adherence. Phosphorylation of focal adhesion kinase (FAK) and Akt, related to integrin-mediated survival, were decreased upon treatment with SeMet-METase while phosphorylation of p38, PKC-delta, and IkappaBalpha increased. In the presence of specific inhibitors of p38, PKC-delta, and NF-kappaB, expression of integrins and cell adhesion to ECM were maintained and cell apoptosis was prevented in SeMet-METase-treated melanoma cells. Treatment with caspase inhibitors restored cell viability and blocked poly (ADP-ribose) polymerase (PARP) cleavage, but did not restore integrin expression and cell adhesion to ECMs reduced by SeMet-METase. Based on these results, we propose that combined treatment with SeMet-METase induces caspase-mediated apoptosis in melanoma cells by altering integrin expression and adhesion. Furthermore, activation of p38, PKC-delta, and NF-kappaB is a prerequisite for the down-regulation of integrin expression, followed by detachment-mediated apoptosis.
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PMID:Methylselenol generated from selenomethionine by methioninase downregulates integrin expression and induces caspase-mediated apoptosis of B16F10 melanoma cells. 1734 6

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22


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