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 influence of tyrosine nitration of cytochrome c and caspase 3 on apoptosis induction was investigated in an established squamous carcinoma cell line, OSC-4. The intracellular NO and O2(-) levels were increased up to about 110-120% and 140-180% of the control levels, respectively, after the treatment of OSC-4 cells with 5-FU (100 microg/ml), PLM (10 microg/ml), CDDP (10 microg/ml), or gamma-rays (20 Gy). The treatment of OSC-4 cells with ONOO(-) (1 mM) and the above anticancer agents induced tyrosine nitration of 14, 32 kDa protein among others and nitration of tyrosine residues of cytochrome c and caspase 3 was identified by the Western blotting of immunoprecipitates obtained by antibodies to these proapoptotic proteins. When cytochrome c and procaspase 3 were treated with ONOO(-), tyrosine nitration was increased in a ONOO(-)-dose dependent manner. Tyrosine nitration of cleaved (17 kDa) caspase 3, however, was not induced by ONOO(-). Procaspase 3 in the cytosol of HeLa cells was activated by the addition of ONOO(-)-treated as well as ONOO(-)-untreated cytochrome c. In addition, cleavage of ICAD and PARP were not suppressed in OSC-4 cells by pretreatment with ONOO(-). Activity of cleaved caspase 3 was not suppressed at low concentrations or by treatment with ONOO(-) or NO donors, SIN-1 and SNP. Furthermore, apoptosis of OSC-4 cells by the anticancer agents was not suppressed by ONOO(-). In conclusion, these results suggest that nitration of tyrosine residues of cytochrome c and procaspase 3 is induced by chemoradiotherapy but their nitration does not suppress cancer cell apoptosis.
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PMID:Tyrosine-nitration of caspase 3 and cytochrome c does not suppress apoptosis induction in squamous cell carcinoma cells. 1251 89

Induction of apoptosis is a hallmark of the cellular response of human lymphocytes and lymphoma cells to treatment with anticancer drugs and irradiation. Both treatment modalities trigger apoptosis through intrinsic, mitochondrial apoptosis pathways resulting in the activation of caspases. We and others have shown that the tyrosine kinase p56/Lck is involved in the regulation of apoptosis induced by irradiation or treatment with ceramide but dispensable for death receptor triggered cell death. However, the role of p56/Lck for apoptosis induction in response to anticancer drugs is unclear. To elucidate the putative requirement of p56/Lck for apoptosis signaling of cytotoxic drugs, activation of caspases and alteration of mitochondrial functions were determined in Jurkat T cells, the p56/Lck deficient JCaM1.6 cells and the p56/Lck retransfected JCaM1.6/Lck cells in response to chemotherapeutic drugs with different targets of their primary action. Treatment with Doxorubicin, Paclitaxel or 5-Fluorouracil induced a breakdown of the mitochondrial membrane potential and apoptotic cell death in p56/Lck expressing Jurkat and the retransfected JCaM1.6/Lck cells within 48h of treatment. However, almost no mitochondrial alterations and no induction of apoptosis could be detected in the p56/Lck deficient JCaM1.6 cells. Correspondingly, activation of caspases-9, -8, and -3 and cleavage of the caspase-3 substrate PARP (poly-(ADP-ribose)-polymerase) were almost completely absent in JCaM1.6 cells while present in p56/Lck positive Jurkat and JCaM1.6/Lck cells. In contrast, retransfection of the cells with the p56/Lck-related tyrosine kinase Src could not restore sensitivity to the treatment with cytotoxic drugs indicating a specific role of the tyrosine kinase p56/Lck in apoptosis signaling. Importantly, kinase-activity of p56/Lck may be dispensable for its pro-apoptoptic action since preincubation with the Src-kinase inhibitor PP2 did not reduce apoptosis induced by cytotoxic drugs. In conclusion, the tyrosine kinase p56/Lck is essential for apoptosis induction by Doxorubicin, Paclitaxel and 5-Fluorouracil regulating early steps of the mitochondrial apoptosis signaling cascade, including alteration of mitochondrial functions and caspase-activation.
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PMID:Involvement of tyrosine kinase p56/Lck in apoptosis induction by anticancer drugs. 1513 Jul 63

Echinomycin, in typical DNA minor groove binder, had comparable efficacy compared to 5-FU in the phase II trail of colon cancer treatment. To improve echinomycin's drawback (hydrophobicity, toxicity), we synthesized the YK-2000 series (echinomycin analogues). Among these, YK-2000 had the best in vitro cytotoxicity on six different human solid cancer cell lines. Echinomycin and YK-2000 were enabled to induce the apoptosis on the HT-29 colorectal cancer cell line. The hypothesis that apoptosis in the HT-29 cell was triggered by echinomycin and YK-2000 were supported through DNA laddering, poly-(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. In order to explore the signaling pathway of echinomycin and YK-2000, we examined the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 MAP kinase. However, what the mechanism of cancer cell death would be induced by echinomycin and YK-2000 is unknown. Here, we present some evidence that one of the major apoptotic signaling pathways induced by echinomycin and YK-2000 is possibly the MAP kinases pathway in HT-29 human colon cancer cells.
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PMID:Echinomycin and a novel analogue induce apoptosis of HT-29 cells via the activation of MAP kinases pathway. 1517 10

The role of the product in the treatment of colorectal cancer is reviewed in the light of experimental and clinical results to date. The fermented wheat germ extract (code name: MSC, trade name: Avemar) registered as a dietary food for special medical purposes for cancer patients to complement the active oncotherapy, exerted a growth inhibitory effect in HCR-25 human colon carcinoma xenograft, and had a synergistic effect with 5-FU in mouse C-38 colorectal carcinoma. The product is capable of chemoprevention of colon carcinoma in F-344 rats. One of the most significant underlying mechanism is a highly cancer cell specific induction of caspase-3 mediated cleavage of PARP. In the frame of supportive therapy, fermented wheat germ extract proved to be efficient in the treatment of colorectal cancer in humans. 30 patients following radical operation were treated with standard postoperative therapy, 12 of them were given fermented wheat germ extract as additive treatment: following a 9 month long administration, no new distant metastases were detected, in contrast to 4 out 18 treated with standard therapy alone. Out of 34 patients following radical surgery and treated with chemotherapy, 17 who were given fermented wheat germ extract, achieved an improved survival rate. In the frame of a controlled multicenter open label cohort study, 170 colorectal cancer patients received anticancer therapies (chemo/radiotherapy) completed with fermented wheat germ extract in 66 of them. Results (fermented wheat germ extract vs. control): new recurrences: 3.0% vs. 17.3% (p < 0.01); new metastases: 7.6% vs. 23.1% (p < 0.01); deaths: 12.1% vs. 31.7% (p < 0.01), progression-related events in total: 16.7% vs. 42.3% (p < 0.001). Survival analysis showed significant improvements in the fermented wheat germ extract group, regarding progression-free (p = 0.0184) and overall survival probabilities (p = 0.0278). Strong predictors of survival determined by Cox's proportional hazards were UICC stage and fermented wheat germ extract treatment. Mild gastrointestinal side effects were observed in 9 cases. Supportive application of fermented wheat germ extract in colorectal cancer is highly recommended.
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PMID:[Fermented wheat germ extract in the supportive therapy of colorectal cancer]. 1625 77

The multi-drug combination of oxaliplatin (OXA), 5-Fluorouracil (5-FU) and leucovorin (LF) is currently considered as the gold standard treatment for metastatic colorectal carcinoma. In previous studies, we have studied a chemotherapy regimen containing gemcitabine (GEM), OXA, LF, and 5-FU (named GOLF regimen) that has shown a good safety profile and highly significant anti-tumor activity. In the present study, we have investigated on the anti-tumour mechanisms of GOLF in human colon cancer HT-29 and WiDr cell lines. We have found that GOLF induced growth inhibition that was largely caused by apoptosis differently from other combinations. Moreover, the different drugs composing GOLF were highly synergistic in inducing growth inhibition. Apoptosis induced by GOLF combination was paralleled by PARP cleavage and caspase 9 and 3 activation that were not recorded in the other combinations. An about 85% decrease of the activity of Erk and Akt was found in GOLF-treated cells. These effects were likely due to decreased expression of the upstream activator Raf-1 and of Akt itself, respectively. The intracellular levels of these signalling components can be post-translationally regulated by ubiquitin-dependent degradation through proteasome. Therefore, we have evaluated the expression of some chaperone components and we have found that GOLF did not affect the expression of both heat shock protein (HSP) 90 and 27 but induced an about 90% increase of HSP70 levels suggesting the inactivation of the multi-chaperone complex. Moreover, an about 4-fold increase of the ubiquitination of Raf-1 was also found and the addition for 12 h of 10 microM proteasome inhibitor lactacystin caused an accumulation of the ubiquitinated isoforms of Raf-1. In conclusions, GOLF was a combination highly synergistic in inducing both growth inhibition and apoptosis of colon cancer cells. These effects likely occurred through the disruption of critical survival pathways and the inactivation of multi-chaperone complex.
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PMID:Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased Raf-1 ubiquitin-dependent degradation. 1629 35

Similar to arsenic trioxide (As2O3), tetra-arsenic oxide (As4O6, TAO) has shown anti-proliferative and apoptosis-inducing effects against human leukemic and solid tumor cells. In order to assess the increase in efficacy, we evaluated the combinatory interaction of TAO combined with paclitaxel, 5-FU or cisplatin and studied its mechanism of action in the cell lines of human gastric, cervix and head and neck tumors. Two agents were combined at equitoxic ratios based on the IC50 of each drug. Efficacy improvement was evaluated using a combination index and isobologram at 50% inhibition level. Apoptosis induction and expression of apoptosis-related proteins was determined and the effect on microtubule polymerization was monitored. TAO combined with paclitaxel showed synergistic interaction in all three of gastric, cervix and head and neck cancer cell lines. On the other hand, TAO when combined with 5-FU or cisplatin showed an antagonistic interaction in head and neck or cervix cancer cell lines, respectively. Simultaneous treatment with TAO with paclitaxel resulted in an increased percentage of apoptotic cells and a significant increase in PARP cleavage and caspase-3 activation in the gastric and cervix cancer cells compared to TAO alone as well as the antagonistic groups (TAO with 5-FU or cisplatin). TAO suppressed the tubulin polymerization in the presence and absence of paclitaxel in a concentration-dependent manner, suggesting mitotic catastrophe as a potential mechanism of the synergism with paclitaxel. Overall, the present study suggests that TAO may have a greater potential as an anti-cancer agent against human gastric, cervix and head and neck tumors, in combination with paclitaxel. The synergistic interaction with paclitaxel may be associated with increased apoptosis via inhibition of paclitaxel-induced tubulin polymerization. Further detailed studies of combinatory mechanisms and evaluation using in vivo models are warranted.
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PMID:Synergistic interaction between tetra-arsenic oxide and paclitaxel in human cancer cells in vitro. 1942 86

Three-dimensional (3D) multicellular tumour spheroids (MTS) have been used as an in vitro model of solid tumours for drug resistance studies because they mimic the growth characteristics of in vivo tumours more closely than in vitro two-dimensional (2D) culture of cancer cell lines. As observed in solid tumours, MTS exhibits a proliferation gradient with outer regions consisting of proliferating cells that surround inner quiescent cells. The innermost cells in core regions undergo cell death mostly by necrosis to form necrotic core due to insufficient supply of oxygen and nutrient such as glucose with increasing size of spheroids. Tumour necrosis is thought to indicate a poor prognosis and to contribute to acquisition of chemoresistance in solid tumours; however, the mechanism underlying necrosis-mediated chemoresistance remains unclear. In this study, we examined the chemoresistance to 5-Fluorouracil (5-FU) using MCF-7 breast cancer MTS. 5-FU (400 microM) induced apoptosis in MCF-7 cell monolayer as determined by HO/PI staining, PARP cleavage, p53 induction, Bax induction, and Bcl-2 down-regulation. When MCF-7 breast tumour spheroids were cultured on agarose for 8 days, they reached approximately 700 microm in diameter, with a necrotic core. We found that 5-FU-induced apoptosis is markedly reduced in spheroids that were cultured for 9 days and had necrotic core, compared with MCF-7 monolayer cells and spheroids that were cultured for 6 days and had no necrotic core, indicating that the formation of necrotic core may be linked to acquisition of chemoresistance to 5-FU. We also found that a specific set of cellular proteins including p53 was aggregated into a RIPA-insoluble form during MTS culture. Furthermore, most of p53 induced by 5-FU was aggregated in MTS with necrotic core. Our results suggest that necrosis-linked p53 aggregation may contribute to acquired apoptotic resistance to 5-FU in MTS model system.
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PMID:Implication of necrosis-linked p53 aggregation in acquired apoptotic resistance to 5-FU in MCF-7 multicellular tumour spheroids. 2051 46

5-Fluorouracil (5-FU) is frequently used in cancer treatment. Previous studies with 5-FU suggest that proapoptotic protein BAX and tumor suppressor protein TP53 are central factors in this process. As the leukemic T cell line Jurkat E6 has mutations in both these genes, we investigated a possible activation of alternative death pathways following 5-FU treatment. Here we show that 5-FU triggers apoptosis in Jurkat cells in a dose-dependent manner. Death responses were only moderately attenuated in the presence of a general caspase inhibitor. However, flow cytometric analysis showed activation of caspase 3 and a slight increase in ROS generation in a time- and dose-dependent manner. Furthermore, we observed 5-FU induced PARP cleavage and notably, reduced expression of antiapoptotic MCL-1L associated with the appearance of proapoptotic MCL-1S. Our results demonstrate the activation of alternative death pathways following treatment with 5-FU, despite mutations in the TP53 and BAX genes.
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PMID:5-fluorouracil-induced death of Jurkat T-cells--a role for caspases and MCL-1. 2103 98

Chemotherapies for colon cancer have recently advanced. However, there is still a need to develop agents and identify effective regimens for better treatments of colon cancer. Histone deacetylase inhibitors (HDACIs) have shown potential as anti-cancer agents. We investigated the anti-tumor effects of CG2 (an HDACI) in combination with irinotecan, 5-FU, or oxaliplatin. Combinations of CG2 with SN38 (the active form of irinotecan), 5FU, or oxaliplatin were more effective than the agents alone when used to inhibit the growth of HCT116 cells. The protein expressions of acetyl-H3, p21, caspase-3, -8, and -9, PARP, and XIAP were affected in a time- and dose-dependent manner in HCT116 cells treated with the CG2 alone or combined CG2 and SN-38. In HCT116 xenografts, the HDACI CG2 in combination with irinotecan dramatically inhibited tumor growth without showing additive toxicity. These data indicate that CG2 together with irinotecan is a promising combination novel treatment for colon cancer.
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PMID:Effects of the HDAC inhibitor CG2 in combination with irinotecan, 5-fluorouracil, or oxaliplatin on HCT116 colon cancer cells and xenografts. 2104 46

5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism. These agents cause imbalances in deoxynucleotide triphosphate levels and the accumulation of uracil and 5-FU in the genome, events that activate the ATR- and ATM-dependent checkpoint signaling pathways and the base excision repair (BER) pathway. Here, we assessed which DNA damage response and repair processes influence 5-FU and FdUrd toxicity in ovarian cancer cells. These studies revealed that disabling the ATM, ATR, or BER pathways using small inhibitory RNAs did not affect 5-FU cytotoxicity. In stark contrast, ATR and a functional BER pathway protected FdUrd-treated cells. Consistent with a role for the BER pathway, the poly(ADP-ribose) polymerase (PARP) inhibitors ABT-888 (veliparib) and AZD2281 (olaparib) markedly synergized with FdUrd but not with 5-FU in ovarian cancer cell lines. Furthermore, ABT-888 synergized with FdUrd far more effectively than other agents commonly used to treat ovarian cancer. These findings underscore differences in the cytotoxic mechanisms of 5-FU and FdUrd and suggest that combining FdUrd and PARP inhibitors may be an innovative therapeutic strategy for ovarian tumors.
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PMID:Poly(ADP-Ribose) polymerase inhibition synergizes with 5-fluorodeoxyuridine but not 5-fluorouracil in ovarian cancer cells. 2161 6


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