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)

ErbB-2 gene encodes tyrosine kinase receptor p185(neu). Overexpression of erbB-2 plays a key role in tumorigenesis or progression such as breast cancer and ovarian cancer. Our previous study showed that ON-III (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone) extracted from Traditional Chinese Medicine Cleistocaly xoperculatus dry flower could inhibit KDR tyrosine kinase phosphorylation and tumor growth in vivo. In this study, we reported that ON-III repressed tyrosine phosphorylation of erbB-2 without reduced erbB-2 receptor expression in MDA-MB-453 cells. Activation of mitogen-activated protein kinase (MAPK) and AKT, downstream molecules of erbB-2-mediated signal transduction pathway, was inhibited following exposure to ON-III. ON-III induced apoptosis in breast cancer cells as determined by caspase-3 and PARP cleavage. Also, ON-III upregulated the expression of proapoptotic BH3-only Bcl-2 family member Bim. Bim siRNA could inhibit ON-III-mediated apoptosis in MDA-MB-453 cells. It concludes that ON-III inhibits erbB-2 tyrosine kinase phosphorylation, shuts down its downstream pathway and triggered apoptosis via induction of Bim. These results suggest that ON-III is a potential novel anti-cancer agent for erbB-2-overexpressing cancer.
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PMID:ON-III inhibits erbB-2 tyrosine kinase receptor signal pathway and triggers apoptosis through induction of Bim in breast cancer cells. 1924 12

Triple negative (TN) breast cancer is more frequent in women who are obese or have type II diabetes, as well as young women of color. These cancers do not express receptors for the steroid hormones estrogen or progesterone, or the type II receptor tyrosine kinase (RTK) Her-2 but do have upregulation of basal cytokeratins and the epidermal growth factor receptor (EGFR). These data suggest that aberrations of glucose and fatty acid metabolism, signaling through EGFR and genetic factors may promote the development of TN cancers. The anti-type II diabetes drug metformin has been associated with a decreased incidence of breast cancer, although the specific molecular subtypes that may be reduced by metformin have not been reported. Our data indicates that metformin has unique anti-TN breast cancer effects both in vitro and in vivo. It inhibits cell proliferation (with partial S phase arrest), colony formation and induces apoptosis via activation of the intrinsic and extrinsic signaling pathways only in TN breast cancer cell lines. At the molecular level, metformin increases P-AMPK, reduces P-EGFR, EGFR, P-MAPK, P-Src, cyclin D1 and cyclin E (but not cyclin A or B, p27 or p21), and induces PARP cleavage in a dose- and time-dependent manner. These data are in stark contrast to our previously published biological and molecular effects of metformin on luminal A and B, or Her-2 type breast cancer cells. Nude mice bearing tumor xenografts of the TN line MDA-MB-231, treated with metformin, show significant reductions in tumor growth (p = 0.0066) and cell proliferation (p = 0.0021) as compared to untreated controls. Metformin pre-treatment, before injection of MDA-MB-231 cells, results in a significant decrease in tumor outgrowth and incidence. Given the unique anti-cancer activity of metformin against TN disease, both in vitro and in vivo, it should be explored as a therapeutic agent against this aggressive form of breast cancer.
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PMID:Metformin induces unique biological and molecular responses in triple negative breast cancer cells. 1971 81

Because DNA methyltransferase (DNMT) inhibitors like azacytidine and decitabine are known to be effective in the clinic for diseases like myelodysplastic syndromes that may result in part from transcriptional dysregulation due to epigenetic changes, there is interest in developing novel DNMT inhibitors that would be more effective and less toxic. The effects of one such agent, zebularine, which inhibits DNMT and cytidine deaminase, were assessed in two human breast cancer cell lines, MDA-MB-231 and MCF-7. Zebularine treatment inhibited cell growth in a dose and time dependent manner with an IC-50 of approximately 100 microM and 150 microM in MDA-MB-231 and MCF-7 cells, respectively, on 96 h exposure. This was associated with increased expression of p21, decreased expression of cyclin-D, and induction of S-phase arrest. At high doses zebularine induced changes in apoptotic proteins in a cell line specific manner manifested by alteration in caspase-3, Bax, Bcl2 and PARP cleavage. Like other DNMT inhibitors, zebularine decreased expression of DNMTs post-transcriptionally as well as expression of other epigenetic regulators like methyl CpG binding proteins and global acetyl H3 and H4 protein levels. Its capacity to reexpress epigenetically silenced genes in human breast cancer cells at low doses was confirmed by its ability to induce expression of estrogen and progesterone receptor mRNA in association with changes suggestive of active chromatin at the ER promoter as evidenced by ChIP. Finally, its effect in combination with other DNMT or HDAC inhibitors like decitabine or vorinostat was explored. The combination of 50 muM zebularine with decitabine or vorinostat significantly inhibited cell proliferation and colony formation in MDA-MB-231 cells compared with either drug alone. These findings suggest that zebularine is an effective DNMT inhibitor and demethylating agent in human breast cancer cell lines and potentiates the effects of other epigenetic therapeutics like decitabine and vorinostat.
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PMID:Effects of a novel DNA methyltransferase inhibitor zebularine on human breast cancer cells. 1945 41

The ischemia/reperfusion (I/R) model in rats allows pharmacological investigation of protective renal effects of certain agents to thereby diminish the incidence of delayed graft function (DGF). The aim of this study was to determine the effects of preconditioning with triiodothyronine (T(3)) on renal function and oxidative status in renal I/R injury. Forty male Wistar rats were preconditioned with T(3) (100 microg/kg) or control (normal saline) at 24 hours prior to 45 minutes of renal ischemia, followed by a 4-hour (groups C-4h and T(3)-4h) or 24-hour (groups C-24h and T(3)-24h) reperfusion period. We determined renal function parameters (urea, creatinine, and proteinuria), oxidative stress biomarkers in plasma (malondialdehyde [MDA], glutathione [GSH], and superoxide dismutase [SOD]), urine (hydrogen peroxide [H(2)O(2)]), and renal tissue (GSH and MDA), and poly(ADP-ribose) polymerase (PARP-1) expression. Proteinuria was significantly lower in the T(3)-treated group (4.63 +/- 1.9 vs 9.27 +/- 0.72 mg/mL/100 g body weight). Pretreated rats showed lower levels of plasma and tissue MDA and urine H(2)O(2) (50.57 +/- 1.17 vs 71.16 +/- 1.14 micromol/100 g body weight). The T(3) treatment was associated with lower postischemia GSH concentrations (3.82 +/- 1.16 vs 4.89 +/- 0.68 nmol/mg protein) and higher SOD levels at 24 hours (11.27 +/- 0.86 vs 9.92 +/- 1.77 nmol/mg protein). Preconditioning with the hormone also reduced PARP-1 tissue expression by 18% (P <or= .05). These findings suggested that preconditioning with T(3) reduced proteinuria, improved lipid peroxidation biomarkers, and increased antioxidant enzyme levels in renal I/R injury.
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PMID:Effect of preconditioning with triiodothyronine on renal ischemia/reperfusion injury and poly(ADP-ribose) polymerase expression in rats. 1971 35

We evaluated the novel gamma-lactam-based analogue, KBH-A145, for its anticancer activities. KBH-A145 markedly inhibited histone deacetylase (HDAC) activity in vitro and in vivo to an extent comparable to suberoyl-anilide hydroxamic acid (SAHA). The proliferation of various types of cancers was significantly suppressed by KBH-A145, among which MDA-MB-231 and MCF, human breast cancer cells and ACHN human renal cancer cells, were most sensitive. This was accompanied by induction of p21(WAF1/Cip1) through compromised recruitment of HDAC1, which leads to hyperacetylation of its promoter region and thus arrested both cells in the G(2)/M phase. Interestingly, this compound induced apoptosis of MDA-MB-231 cells, but not ACHN cells, through cleavage of poly(ADP-ribose) polymerase (PARP). Taken together, these results show that this novel gamma-lactam-based HDAC inhibitor potently inhibits the growth of human breast and renal cancer cells. Thus KBH-A145 is a potential therapeutic agent for the treatment of these types of cancer.
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PMID:A novel gamma-lactam-based histone deacetylase inhibitor potently inhibits the growth of human breast and renal cancer cells. 1980 34

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

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. However, sensitivity of cancer cells for induction of apoptosis by TRAIL varies considerably. Therefore, it is important to develop agents that overcome this resistance. We show, for the first time, that eupatolide, the sesquiterpene lactone isolated from the medicinal plant Inula britannica, sensitizes human breast cancer cells to TRAIL-induced apoptosis. Treatment with TRAIL in combination with subtoxic concentrations of eupatolide enhanced the TRAIL-induced cytotoxicity in MCF-7, MDA-MB-231 and MDA-MB-453 breast cancer cells, whereas each reagent alone slightly induced cell death. The combination induced sub-G1 phase DNA content and annexin V-staining in MCF-7 cells, which are major features of apoptosis. Apoptotic characteristics induced by the combined treatment were significantly inhibited by a pan-caspase inhibitor. The sensitization to TRAIL-induced apoptosis was accompanied by the activation of caspase-8 and was concomitant with Bid and poly(ADP-ribose) polymerase (PARP) cleavage. Treatment of eupatolide alone significantly down-regulated the expression of cellular FLICE inhibitory protein (c-FLIP) in MCF-7 cells. Furthermore, enforced expression of c-FLIP significantly attenuated the apoptosis induced by this combination in MCF-7 cells, suggesting a key role for c-FLIP down-regulation in these events. We also observed that euaptolide inhibited AKT phosphorylation in a dose- and time-dependent manner. Moreover, inhibition of Akt by LY294002, a specific PI3K inhibitor, down-regulated c-FLIP expression in MCF-7 cells. Taken together, these results indicate that eupatolide could augment TRAIL-induced apoptosis in human breast cancer cells by down-regulating c-FLIP expression through the inhibition of AKT phosphorylation and be a valuable compound to overcome TRAIL resistance in breast cancer cells.
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PMID:The sesquiterpene lactone eupatolide sensitizes breast cancer cells to TRAIL through down-regulation of c-FLIP expression. 1995 87

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

Garcinol, obtained from Garcinia indica in tropical regions, is used for its numerous biological effects. Its anti-cancer activity has been suggested but the mechanism of action has not been studied in-detail, especially there is no report on its action against breast cancer cells. Here we tested our hypothesis that garcinol may act as an anti-proliferative and apoptosis-inducing agent against breast cancer cell lines. Using multiple techniques such as MTT, Histone-DNA ELISA, Annexin V-PI staining, Western blot for activated caspases and cleaved PARP, homogenous caspase-3/7 fluorometric assay and EMSA, we investigated the mechanism of apoptosis-inducing effect of garcinol in ER-positive MCF-7 and ER-negative MDA-MB-231 cells. We found that garcinol exhibits dose-dependent cancer cell-specific growth inhibition in both the cell lines with a concomitant induction of apoptosis, and has no effect on non-tumorigenic MCF-10A cells. Our results suggested induction of caspase-mediated apoptosis in highly metastatic MDA-MB-231 cells by garcinol. Down-regulation of NF-kappaB signaling pathway was observed to be the mechanism of apoptosis-induction. Garcinol inhibited constitutive NF-kappaB activity, which was consistent with down-regulation of NF-kappaB-regulated genes. This is the first report on anti-proliferative and apoptosis-inducing action of garcinol against human breast cancer cells and the results suggest that this natural compound merits investigation as a potential chemo-preventive/-therapeutic agent, especially against breast cancer.
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PMID:Apoptosis-inducing effect of garcinol is mediated by NF-kappaB signaling in breast cancer cells. 2010 49

The emergence of silymarin (SMN) as a natural remedy for liver diseases, coupled with its entry into NIH clinical trial, signifies its hepatoprotective potential. SMN is noted for its ability to interfere with apoptotic signaling while acting as an antioxidant. This in vivo study was designed to explore the hepatotoxic potential of Doxorubicin (Dox), the well-known cardiotoxin, and in particular whether pre-exposures to SMN can prevent hepatotoxicity by reducing Dox-induced free radical mediated oxidative stress, by modulating expression of apoptotic signaling proteins like Bcl-xL, and by minimizing liver cell death occurring by apoptosis or necrosis. Groups of male ICR mice included Control, Dox alone, SMN alone, and Dox with SMN pre/co-treatment. Control and Dox groups received saline i.p. for 14 days. SMN was administered p.o. for 14 days at 16 mg/kg/day. An approximate LD(50) dose of Dox, 60 mg/kg, was administered i.p. on day 12 to animals receiving saline or SMN. Animals were euthanized 48 h later. Dox alone induced frank liver injury (>50-fold increase in serum ALT) and oxidative stress (>20-fold increase in malondialdehyde [MDA]), as well as direct damage to DNA (>15-fold increase in DNA fragmentation). Coincident genomic damage and oxidative stress influenced genomic stability, reflected in increased PARP activity and p53 expression. Decreases in Bcl-xL protein coupled with enhanced accumulation of cytochrome c in the cytosol accompanied elevated indexes of apoptotic and necrotic cell death. Significantly, SMN exposure reduced Dox hepatotoxicity and associated apoptotic and necrotic cell death. The effects of SMN on Dox were broad, including the ability to modulate changes in both Bcl-xL and p53 expression. In animals treated with SMN, tissue Bcl-xL expression exceeded control values after Dox treatment. Taken together, these results demonstrated that SMN (i) reduced, delayed onset, or prevented toxic effects of Dox which are typically associated with hydroxyl radical production, (ii) performed as an antioxidant limiting oxidative stress, (iii) protected the integrity of the genome, and (iv) antagonized apoptotic and necrotic cell death while increasing antiapoptotic Bcl-xL protein levels and minimizing the leakage of proapoptotic cytochrome c from liver mitochondria. These observations demonstrate the protective actions of SMN in liver, and raise the possibility that such protection may extend to other organs during Dox treatment including the heart.
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PMID:Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver. 2014 34


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