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)

Alkannin is the major bioactive compound of Arnebia euchroma roots, which is used in many therapeutic remedies in Chinese traditional medicine. SYUNZ-16 is a new derivative of alkannin. In this study, anticancer effects of SYUNZ-16 on human lung adenocarcinoma cell line GLC-82 and human hepatocarcinoma cell line Hep3B were tested in vitro. The results showed SYUNZ-16 could obviously inhibit the proliferation of these cancer cell lines via induction of apoptosis, with the evidence of increasing AnnexinV-positive cells and cleaved caspase-3 and PARP fragments. More importantly, we found that SYUNZ-16 could inhibit AKT activity in cell-free system. Treatment of cancer cells with SYUNZ-16 decreased the phosphorylation of AKT. Additionally, SYUNZ-16 partially attenuated the phosphorylation levels of FKHR and FKHRL1 in a dose-dependent and time-dependent fashion, and led to an increase in the nuclear accumulation of exogenous FKHR, and upregulated the mRNA expression of Bim and TRADD in cancer cells. Further study showed that constitutively activated AKT1 transfection could reduce apoptosis induction mediated by SYUNZ-16. The in vivo experiments showed that SYUNZ-16 had inhibitory effects on S-180 sarcoma implanted to mice. And in GLC-82 xenograft models, SYUNZ-16 at 20 mg/kg/qod remarkably inhibited the tumor growth with the T/C value of 45.3%. Taken together, SYUNZ-16 might be a potent inhibitor of AKT signaling pathway in tumor cells. These data provide evidence for the development of SYUNZ-16 as a potential antitumor drug candidate for further research and development.
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PMID:SYUNZ-16, a newly synthesized alkannin derivative, induces tumor cells apoptosis and suppresses tumor growth through inhibition of PKB/AKT kinase activity and blockade of AKT/FOXO signal pathway. 1990 42

Presented experiment considers combination of genistein and photodynamic therapy with hypericin with a view to achieve higher therapeutic outcome in human breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, both identified in our conditions as photodynamic therapy resistant. Since genistein is known to suppress Bcl-2 expression, we predicted that photodynamic therapy with hypericin might benefit from mutual therapeutic combination. In line with our expectations, combined treatment led to down-regulation of Bcl-2 and up-regulation of Bax in both cell lines as well as to suppression of Akt and Erk1/2 phosphorylation induced by photoactivated hypericin in MCF-7 cells. Although Akt and Erk1/2 phosphorylation was not stimulated by photodynamic therapy with hypericin in MDA-MB-231 cells, it was effectively suppressed in combination. Variations in cell death signaling favoring apoptosis were indeed accompanied by cell cycle arrest in G(2)/M-phase, activation of caspase-7, PARP cleavage and increased occurrence of cells with apoptotic morphology of nucleus. All these events corresponded with suppression of proliferation and significantly lowered clonogenic ability of treated cells. In conclusion, our results indicate that pre-treatment with tyrosine kinase inhibitor genistein may significantly improve the effectiveness of photodynamic therapy with hypericin in MCF-7 and MDA-MB-231 breast cancer cells.
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PMID:Down-regulation of Bcl-2 and Akt induced by combination of photoactivated hypericin and genistein in human breast cancer cells. 1993 26

Photodynamic therapy (PDT) is a flexible multi-target therapeutic approach. One of the main requirements of successful PDT is sufficient intracellular concentration of an applicable photosensitizer. Mechanisms of anticancer drug elimination by tumour cells are mostly linked to the elevated expression and activity of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and P450 monooxygenases. The interaction of hypericin with this cell drug-defence system is still unclear. We report here for the first time increased activity of MRP1 and BCRP in HT-29 colon cancer cells treated with hypericin per se. On the contrary, pre-treatment with proadifen (SKF525A) affected the function of MRP1 and BCRP leading to increased hypericin content, which might indicate a possible link between proadifen and these ABC transporter proteins. Subsequent enhanced intracellular oxidative stress was accompanied by loss of mitochondrial membrane potential, activation of caspase-9 and -3, PARP cleavage and onset of apoptosis. In conclusion, our study suggests that drug efflux transporters MRP1 and BCRP affect the pharmacokinetics of hypericin in HT-29 colon adenocarcinoma cells, and the action of hypericin-mediated PDT (HY-PDT) should be modulated by pre-treatment with their specific inhibitors.
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PMID:Drug efflux transporters, MRP1 and BCRP, affect the outcome of hypericin-mediated photodynamic therapy in HT-29 adenocarcinoma cells. 2002 69

The use of ultra-diluted natural products in the management of disease and treatment of cancer has generated a lot of interest and controversy. We conducted an in vitro study to determine if products prescribed by a clinic in India have any effect on breast cancer cell lines. We studied four ultra-diluted remedies (Carcinosin, Phytolacca, Conium and Thuja) against two human breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) and a cell line derived from immortalized normal human mammary epithelial cells (HMLE). The remedies exerted preferential cytotoxic effects against the two breast cancer cell lines, causing cell cycle delay/arrest and apoptosis. These effects were accompanied by altered expression of the cell cycle regulatory proteins, including downregulation of phosphorylated Rb and upregulation of the CDK inhibitor p27, which were likely responsible for the cell cycle delay/arrest as well as induction of the apoptotic cascade that manifested in the activation of caspase 7 and cleavage of PARP in the treated cells. The findings demonstrate biological activity of these natural products when presented at ultra-diluted doses. Further in-depth studies with additional cell lines and animal models are warranted to explore the clinical applicability of these agents.
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PMID:Cytotoxic effects of ultra-diluted remedies on breast cancer cells. 2004 74

Previous studies suggest that the n-3 polyunsaturated fatty acids (PUFAs) eicosapenteinoic acid (EPA) and docosahexaenoic acid (DHA), constituents of fish oil, exert chemopreventive activity in colon cancer. One of the mechanisms involved is the facilitation of apoptosis. While a pro-apoptotic potential of n-3 PUFAs has been suggested, it is still unclear whether additional consumption of fish will also lead to comparable results. The aim of this study was to assess EPA- and DHA-mediated effects on endpoints of apoptosis and to use a novel biomarker-approach to measure modulation of apoptosis by consumption of fish. LT97 human colon adenoma and HT29 human colon adenocarcinoma cells were used to investigate modulation of apoptosis by EPA, DHA or linoleic acid (LA) using a set of endpoints, namely phosphatidylserine staining with Annexin-V (flow cytometry), Bcl-2 expression (Real-time RT-PCR), and Bid, caspase 3, 8 and 9 expression as well as PARP cleavage (Western Blot). Furthermore, faecal water (FW) of volunteers (n = 89) from a human trial intervening with fish was used to investigate changes in apoptosis by flow cytometry. DHA was more effective at inducing apoptosis than EPA. LT97 cells were more prone to DHA and EPA induced apoptosis than HT29 cells. Treatment of LT97 cells with FW from volunteers consuming fish did not result in any changes in apoptosis. Taken together, our results show that adenoma cells are highly susceptible to n-3 PUFA-induced apoptosis. By using a biomarker-approach (FW) to measure apoptosis-induction ex vivo no change in apoptosis after additional fish consumption was detectable.
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PMID:Fish fatty acids alter markers of apoptosis in colorectal adenoma and adenocarcinoma cell lines but fish consumption has no impact on apoptosis-induction ex vivo. 2010

Apoptosis has been shown to be induced by many agents, including the clinically useful Sorafenib and K vitamins (VKs). Since few agents have activity against pancreas cancer cell growth, we evaluated the role of naturally occurring K vitamins and Sorafenib both independently and together on the growth in culture of pancreas adenocarcinoma cell lines, including PL-5, PANC-1, and MIA PaCa-2. We found that when a K vitamin was combined with Sorafenib, the dose of Sorafenib required for growth inhibition was substantially reduced. Furthermore, growth could be inhibited at doses of each VK plus Sorafenib in combination that were ineffective when used alone. This effect was seen using vitamins K1, K2, and K5. The combination of VK1 plus Sorafenib-induced apoptosis, as determined by both FACS and TUNEL staining. Phospho-ERK and Bcl-2 levels were decreased, but not levels of other bcl-2 family members. Cleavage of caspases 3 and 8, PARP and Bid were all induced by this combination. Vitamin K1 plus Sorafenib combination also resulted in elevated levels of activated c-Jun N-terminal kinase (JNK) and its substrates c-Jun and FasL. JNK inhibition partly antagonized the induction of apoptosis. Thus, combination VK1 plus Sorafenib strongly induced growth inhibition and apoptosis in pancreas cancer cells, involving both inhibition of the RAF/MEK/ERK pathway as well as activation of the JNK, c-Jun and FasL apoptotic pathway. Since both agents are available for human use, the combination is attractive for evaluation against pancreas cancer growth in vivo.
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PMID:Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways. 2030 Nov 94

Several studies have shown that curcumin can induce apoptosis and inhibit growth in human tumor cell lines. However, the mechanism is not completely understood yet. The present studies were designed to investigate the effects of curcumin on human A549 lung adenocarcinoma cells lines to better understand its effect on apoptosis and apoptosis-related genes in vitro. Apoptosis induction, mitochondria membrane potential, mitochondria structure, and apoptotic associated gene expression were examined by flow cytometric assay, confocal microscopy, Western blotting and electron microscopy. After treatment with curcumin, percentage of apoptotic cells increased dose- and time-dependently, and morphology observation revealed typical apoptotic features. Our data further indicated that the expression of Bax proteins in A549 cells was increased in a dose-dependent manner, whereas the expression of Bcl-2 was significantly decreased, thus the ratio of Bax/Bcl-2 was increased. The apoptotic process was accompanied by the change of mitochondrial function and structure which led to release of the cytochrome c, and activation of caspase-9 and caspase-3. Furthermore, curcumin also induced a dose-dependent cleavage of PARP. Caspases activation during the course of curcumin-induced apoptosis was additionally confirmed by using a broad-spectrum caspases inhibitor, Z-VAD-fmk. As expected, the inhibitor was able to decrease curcumin-induced apoptosis on A549 cells. These results suggested that mitochondria played an important role in the curcumin-induced apoptosis, and mitochondria membrane potential loss initiated apoptosis via the activation of caspases.
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PMID:Curcumin induces mitochondria pathway mediated cell apoptosis in A549 lung adenocarcinoma cells. 2037 42

In the present study, we investigated the response of A549 (non-small cell lung-cancer), HepG2 (human hepatoma) and MCF-7 (human breast adenocarcinoma) cell lines to treatment with aclarubicin (ACL). The aim of this research was to compare the ability of ACL to induce apoptosis or necrosis in solid tumours. The mode of cell death induced by ACL was evaluated by flow-cytometry and fluorescence microscopy. We show that the drug induced both apoptosis and necrosis in the cells. Apoptotic cell death was associated with morphological changes, DNA fragmentation, changes in activity of poly(ADP-ribose)polymerase (PARP) and drug-mediated activation of caspase-3 and caspase-8. The occurrence of all these events was time-dependent. The extent of apoptosis was also dependent on the kind of cell line, the sensitivity to ACL and the intracellular drug content. This study demonstrates that the cells most sensitive to ACL, A549, accumulated a significantly higher level of the drug and were also more susceptible to apoptosis than the other cells. In contrast, the relatively less sensitive HepG2 and MCF-7 cell lines appeared more resistant to apoptosis induction. On the basis of these results, it seems that aclarubicin is able to induce apoptosis in human solid tumours.
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PMID:Aclarubicin-induced apoptosis and necrosis in cells derived from human solid tumours. 2039 85

Toona sinensis (TS), which is also known as Cedrela sinensis, belongs to Meliaceae family, the compounds identified from this TS leaves possess a wide range of biologic functions, such as hypoglycemic effects, anti-LDL glycative activity, antioxidant activities, and inhibition of sudden acute respiratory syndrome (SARS) coronavirus replication. However, their effect against cancer cells is not well explored. In this study, to understand the cytotoxic effect and molecular mechanism stimulated by TSL-1 (TS leaf extract fraction) we employed three different non-small-cell lung cancer (NSCLC) cell lines: H441 cells (lung adenocarcinoma), H661 cells (lung large cell carcinoma) and H520 cells (lung squamous cell carcinoma). IC50 value was varied between these three cell lines, the least IC(50) value was observed in TSL-1-treated H661cells. Exposure of NSCLC cells to TSL-1 caused cell-cycle arrest in subG1 phase and caused apoptosis. Moreover, TSL-1 treatment decreased the cell-cycle regulators; cyclin D1 and CDK4 proteins by up regulating p27 expression in a dose-dependent manner. Thus, the TSL-1-induced apoptosis was further confirmed by cell morphology, subG1 peak accumulation, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) cleavage, propidium iodide (PI)-Annexin-V double staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The decreased Bcl2 protein level was concurrent with an increased Bax protein level in all 3 cell lines. Additionally, the tumoricidal effect of TSL-1 was measured using a xenograft model, after 5 weeks of TSL-1 treatment by various regimen caused regression of tumor. Taken together both these in vitro and in vivo studies revealed that TSL-1 is a potent inhibitor against NSCLC growth and our provoking result suggest that TSL-1 can be a better nutriceutical as a singlet or along with doublet agents (taxane, vinorelbine, and gemcitabine) for treating NSCLC.
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PMID:Antiproliferative effect of Toona sinensis leaf extract on non-small-cell lung cancer. 2047 45

The proteasome inhibitor bortezomib (B) has been shown to enhance gemcitabine (G) effects against pancreatic ductal adenocarcinoma (PDAC). Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic cytokine. We tested the combination effects of bortezomib, gemcitabine and EMAP in experimental PDAC. Bortezomib inhibited the in vitro proliferation of PDAC and endothelial cells, with additive effects in combination with gemcitabine or EMAP. Bortezomib induced apoptosis as observed by PARP-1 cleavage; it also increased the expression of p21 (>27-fold) and p27 (>2.5-fold), with additive effects in combination with gemcitabine and EMAP. Bortezomib caused a decrease in the expression of the antiapoptotic protein Bcl-2, and an increase in the proapoptotic protein Bax and in p53. Bortezomib had no effect on the intracellular levels of full length or mature EMAP. An in vivo murine xenograft model showed extended survival in all combination groups except B + E compared with control or monotherapy, but no benefit of B + E + G over E + G. The relative local tumor growth compared to controls after bortezomib, EMAP, gemcitabine, B + G, E + G or B + E + G was 92, 52, 48, 36, 18 and 35%, respectively. Our results show that in vitro bortezomib had an antiproliferative and proapoptotic effect, and it's combination with gemcitabine and EMAP increased these effects. In vivo, bortezomib had no antitumor effect by itself, enhanced gemcitabine effects in combination, but failed to further significantly improve the E + G combination benefit. The potential value of proteasome inhibition in experimental therapy approaches for PDAC appears to relate primarily to the combination with the cytotoxic drug rather than with the antiendothelial agent.
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PMID:Combination effects of bortezomib with gemcitabine and EMAP II in experimental pancreatic cancer. 2058 50


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