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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report on the individual and combined effects of doxorubicin (DOX) and hyperthermia (HYP) on nucleoid sedimentation and poly (ADP-ribose) polymerase (PARP) activity of L1210 cells. The effects of HYP and DOX on nucleoid sedimentation (increased sedimentation) were similar and correlated with cell viability. No correlation of PARP activity with cell toxicity was evident; the activity of PARP was inhibited by HYP (42 degrees C; 1-3 h) and stimulated by DOX (1-10 microM; 30 min). The HYP-induced inhibition of PARP was actually ameliorated by simultaneous exposure to DOX. Although separate studies have previously suggested that chromatin alterations or the inhibition of PARP might play a role in the effect of HYP, the correlation of nucleoid changes (rather than PARP activity) with cell viability emphasizes the contribution of the former. Furthermore, the results suggest that the nucleoid technique may prove useful in screening potential treatment modalities.
Cancer Chemother Pharmacol 1988
PMID:Effect of hyperthermia and doxorubicin on nucleoid sedimentation and poly (ADP-ribose) polymerase activity in L1210 cells. 312 5

Poly(ADP-ribose) polymerase (PARP) plays an important role in a number of cellular processes including DNA repair. Since poly(ADP-ribosyl)ation occurs in response to radiation- or drug-induced DNA damage, inhibitors of the enzyme may enhance the antitumour activity of radiotherapy or cytotoxic drug treatment. In this review the development of PARP inhibitors is discussed, and structure-activity relationships amongst inhibitors of the enzyme are presented. Studies to date regarding the in vitro and in vivo activity of PARP inhibitors, as resistance modifying agents in cancer therapy, are also overviewed.
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PMID:The role of inhibitors of poly(ADP-ribose) polymerase as resistance-modifying agents in cancer therapy. 757 23

We have used two different approaches to study the consequences of NAD/poly(ADP-ribose) deficiency on p53 expression and its activity in V79-derived cell lines. In the first approach, we have used two cell lines that are deficient in poly(ADP-ribose) (pADPR) synthesis because of deficiency in the enzyme poly(ADP-ribose) polymerase (PARP). In a second approach, we have used a cell line that is deficient in NAD/pADPR metabolism due to unavailability of NAD, the substrate for PARP. These NAD/PARP-deficient cell lines exhibit a significant reduction in both baseline p53 expression and its activity compared to their parental V79 cells. Furthermore, etoposide, a topoisomerase II inhibitor that was shown to cause an increase in p53 expression and subsequent apoptosis in V79 cells, failed to produce any significant increase in p53 expression or apoptotic DNA fragmentation in NAD/PARP-deficient cell lines. Thus, our studies suggest that NAD/pADPR synthesis may be involved in the regulation of p53 and its dependent pathways.
Cancer Res 1995 Sep 01
PMID:Involvement of NAD-poly(ADP-ribose) metabolism in p53 regulation and its consequences. 764 Nov 78

At a concentration of 2.5 mM, nicotinamide (NA), an inhibitor of poly(ADP-ribose) polymerase (PARP), significantly potentiated the cytotoxicity of cisplatin (DDP) in a DDP-resistant rat ovarian tumor cell line (O-342/DDP) in vitro, whereas the same treatment had no substantial effect on DDP's cytotoxic activity against the DDP-sensitive parental line (O-342). Furthermore, in a nude mouse model where the O-342/DDP tumor grew intraperitoneally, whereas DDP given alone at 1 mg/kg x 3 exhibited no antitumor activity as compared with control values due to the resistance, NA given at a nontoxic dose (5 mmol/kg x3) significantly increased the mean survival time (MST) of the tumor-bearing NMRI nude mice from 20.7 days in the DDP-treated group to 29.0 days in the combination group. Mechanism studies showed that endogenous PARP activity (incorporation of tritiated nicotinamide adenine dinucleotide, [3H]-NAD) was 2.6 times higher in O-342/DDP than in O-342 cells and that the presence of 2.5 mM NA during the incubation with the isotope resulted in 73.3% inhibition of the enzyme activity in O-342/DDP cells but in only about 30% inhibition in the sensitive line. However, treatment with NA during and after DDP exposure failed to produce any significant effect on the formation of DNA single-strand breaks (SSB) but decreased the induction of DNA interstrand cross-links (ISCL) by DDP in the sensitive and resistant cell lines. These results suggest that NA might have some clinical potential in reversing DDP resistance, and further studies are therefore warranted to confirm the resistance-reversing effect of NA in other DDP-resistant cell lines.
Cancer Chemother Pharmacol 1993
PMID:Reversal of acquired cisplatin resistance by nicotinamide in vitro and in vivo. 826 76

Recent evidence suggests that mammalian cysteine proteases related to Caenorhabditis elegans CED-3 are key components of mammalian programmed cell death or apoptosis. We have shown recently that the CPP32 and Mch2 alpha cysteine proteases cleave the apoptotic markers poly(ADP-ribose) polymerase (PARP) and lamins, respectively. Here we report the cloning of a new Ced-3/interleukin 1 beta-converting enzyme-related gene, designated Mch3, that encodes a protein with the highest degree of homology to CPP32 compared to other family members. An alternatively spliced isoform, named Mch3 beta, was also identified. Bacterially expressed recombinant Mch3 has intrinsic autocatalytic/autoactivation activity. The specific activity of Mch3 alpha toward the peptide substrate DEVD-7-amino-4-methylcoumarin and PARP resembles that of CPP32. Like interleukin 1 beta-converting enzyme and CPP32, the active Mch3 alpha is made of two subunits derived from a precursor (proMch3 alpha). It was of interest that recombinant CPP32-p17 subunit can form an active heteromeric enzyme complex with recombinant Mch3 alpha-p12 subunit and vice versa, as determined by the ability of the heteromeric complexes to induce apoptosis in Sf9 cells. These data suggest that proMch3 alpha and proCPP32 can interact to form an active Mch3 alpha/CPP32 heteromeric complex. We also provide evidence that CPP32 can efficiently cleave proMch3 alpha, but not the opposite, suggesting that Mch3 alpha activation in vivo may depend in part on CPP32 activity. The high degree of conservation in structure and specific activity and the coexistence of Mch3 alpha and CPP32 in the same cell suggests that the PARP cleavage activity observed during apoptosis cannot solely be attributed to CPP32 but could also be an activity of Mch3 alpha.
Cancer Res 1995 Dec 15
PMID:Mch3, a novel human apoptotic cysteine protease highly related to CPP32. 852 91

Poly(ADP-ribose) polymerase (PARP) is an evolutionally conserved nuclear protein present in most eukaryotic species and catalyzes the formation of ADP-ribose polymers covalently attached to proteins. PARP is strongly activated by DNA single- or double-strand breaks and is thought to be involved in cellular responses to DNA damage. Based on the SV40-transformed Chinese hamster cell line CO60, we had established stable transfectants that overexpress the PARP DNA-binding domain conditionally. DNA-binding domain overexpression led to trans-dominant inhibition of poly(ADP-ribosyl)ation and sensitized the cells to genotoxic agents. Using the amplification of chromosomally integrated SV40 DNA as an indicator system, we show here that trans-dominant PARP inhibition potentiates genetic instability induced by N-methyl-N'-nitro-N-nitrosoguanidine treatment of cells.
Cancer Res 1996 Jun 15
PMID:Trans-dominant inhibition of poly(ADP-ribosyl)ation potentiates carcinogen induced gene amplification in SV40-transformed Chinese hamster cells. 866

3-Aminobenzamide (3-ABA) is an inhibitor of poly(ADP-ribose)polymerase (PARP), an enzyme involved in several cellular processes, and exerts its effects by acting at the cytoskeleton level. Here we show that 3-ABA has an antiproliferative effect on the human carcinoma cell line A431, as measured by different assays. 3-ABA was capable of inhibiting cell growth as well as colony formation, this inhibitory effect is reversible. Morphological analyses showed a series of cellular alterations, such as a remarkable increase of dendritic-like protrusions, quite unusual in epithelial cells, and suggestive of a differentiative triggering. Immunocytochemical studies suggested that a major target of 3-ABA was indeed the cytoskeleton. These data, together with those of the literature, indicate that 3-ABA, depending on cell histotype and drug concentration, is a versatile drug capable of exerting antiproliferative and cytostatic effects as well as cytotoxic and antiapoptotic effects, processes sharing an important involvement of cytoskeleton. These unique characteristics of 3-ABA may be of interest for cancer research.
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PMID:Antiproliferative activity of 3-aminobenzamide in A431 carcinoma cells is associated with a target effect on cytoskeleton. 878 Jun 97

Ara-C has been shown to induce apoptosis of human acute myelogenous leukemia HL-60 cells. The DNA repair enzyme poly(ADP-ribose) polymerase (PARP) is known to be degraded during apoptosis. PARP as a substrate is cleaved by the Yama protease, encoded by the CPP32beta/Yama gene. Yama belongs to the interleukin 1beta converting enzyme/ced-3 family of cysteine proteases that are activated as a cascade, producing proteolytic cleavage of specific substrates that results in the morphological and biochemical features of apoptosis. In the present studies, we determined the effect of high intracellular levels of the antiapoptosis Bcl-2 or Bcl-xL protein on Yama protease activation and PARP degradation during Ara-C-induced apoptosis. For this, we utilized HL-60/Bcl-2, HL-60/Bcl-xL, or control HL-60/neo cells, which were created by transfection of the cDNA of the bcl-2, bcl-xL, or the neomycin-resistant genes, respectively. As compared to HL-60/neo, HL-60/Bcl-2 and HL-60/Bcl-xL cells have 5-fold greater expression of Bcl-2 and Bcl-xL, respectively. However, these cell lines have similar levels of p32Yama and PARP. Treatment with 10 or 100 microM Ara-C for 4 h produced DNA fragmentation and morphological features of apoptosis in HL-60/neo cells. This was associated with the cleavage and activation of p32Yama and PARP degradation but not with the induction of Yama mRNA. In contrast, in HL-60/Bcl-2 and HL-60/ Bcl-xL cells, Ara-C-induced p32Yama activation by its cleavage, PARP degradation and apoptosis were significantly inhibited. High Bcl-2 and Bcl-xL levels in these cells also inhibited Yama protease activity, PARP degradation, and apoptosis due to clinically relevant concentrations of etoposide and mitoxantrone. These results suggest that the activation of the Yama protease and PARP degradation are involved in Ara-C-, etoposide-, or mitoxantrone-induced apoptosis. In addition, they suggest that Bcl-2 and Bcl-xL antagonize drug-induced apoptosis by a mechanism that interferes in the activity of a key cysteine protease that is involved in the execution of apoptosis.
Cancer Res 1996 Oct 15
PMID:Overexpression of Bcl-2 or Bcl-xL inhibits Ara-C-induced CPP32/Yama protease activity and apoptosis of human acute myelogenous leukemia HL-60 cells. 884 Sep 93

O6-benzylguanine (O6-BG) and 3-aminobenzamide (3-AB) inhibit the DNA repair proteins O6-alkylguanine-DNA alkyltransferase (AGT) and poly(ADP-ribose) polymerase (PARP) respectively. The effect of O6-BG and/or 3-AB on temozolomide and 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) cytotoxicity, was assessed in seven human tumour cell lines: six with an AGT activity of > 80 fmol mg-1 protein (Mer+) and one with an AGT activity of < 3 fmol mg-1 protein (Mer-). Three of the Mer+ cell lines (LS174T, DLD1 and HCT116) were considered to exhibit resistance to methylation by a mismatch repair deficiency (MMR-), each being known to exhibit microsatellite instability, and DLD1 and HCT116 having well-characterised defects in DNA mismatch binding. Potentiation was defined as the ratio between an IC50 achieved without and with a particular inhibitor treatment. Temozolomide or BCNU cytotoxicity was not potentiated by either inhibitor in the Mer- cell line. Preincubation with O6-BG (100 microM for 1 h) was found to potentiate the cytotoxicity of temozolomide by 1.35- to 1.57-old in Mer+/MMR+ cells, but had no significant effect in Mer+/MMR- cells. In comparison, O6-BG pretreatment enhanced BCNU cytotoxicity by 1.94- to 2.57-fold in all Mer+ cell lines. Post-incubation with 3-AB (2 mM, 48 h) potentiated temozolomide by 1.35- to 1.59-fold in Mer+/MMR+ cells, and when combined with O6-BG pretreatment produced an effect which was at least additive, enhancing cytotoxicity by 1.97- to 2.16-fold. 3-AB treatment also produced marked potentiation (2.20- to 3.12-fold) of temozolomide cytotoxicity in Mer+/MMR- cells. In contrast, 3-AB produced marginal potentiation of BCNU cytotoxicity in only three cell lines (1.19- to 1.35-fold), and did not enhance the cytotoxicity of BCNU with O6-BG treatment in any cell line. These data suggest that the combination of an AGT and PARP inhibitor may have a therapeutic role in potentiating temozolomide activity, but that the inhibition of poly(ADP-ribosyl)ation has little effect on the cytotoxicity of BCNU.
Br J Cancer 1996 Oct
PMID:3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity. 885 70

Recent evidence suggests that members of the interleukin-1-beta-converting enzyme (ICE)/Ced-3 family are key mediators of mammalian apoptosis. The known members of the ICE/Ced-3 cysteine protease family are synthesized as proenzymes and require proteolytic processing to produce active, heterodimeric enzymes. The baculovirus protein P35 has recently been shown to inhibit several members of the ICE/Ced-3 cysteine protease family. The importance of ICE/Ced-3 cysteine proteases in programmed cell death prompted us to investigate the role of the apoptotic mediator, CPP32, in the glucocorticoid-mediated cell death pathway. Glucocorticoids induce growth inhibition and apoptosis in sensitive leukemic cell lines, immature thymocytes, and eosinophils. In this report, we demonstrate the enzymatic cleavage of proCPP32 to its active subunits in cells undergoing glucocorticoid-induced apoptotic cell death. Concurrently, in apoptotic cells, PARP, a 116-kilodalton (kDa) human poly(ADP-ribose) polymerase, is proteolytically cleaved to its signature 85-kDa fragment. The proteolytic processing of PARP (the nuclear DNA repair enzyme known to be cleaved in association with apoptosis) is catalyzed by members of the ICE/Ced-3 family. Importantly, stable transfection of the antiapoptotic baculovirus P35 inhibits glucocorticoid-induced apoptotic cell death, proteolytic processing of proCPP32, and cleavage of the 116kDa PARP. We conclude that activation of CPP32 is a critical event in glucocorticoid-induced apoptosis and that this pathway is inhibited at or upstream of CPP32 by baculovirus P35. These data demonstrate that PARP cleavage occurs during glucocorticoid-induced apoptotic cell death and show that this proteolytic process is blocked by the expression of baculovirus P35, supporting a role for activation of the ICE/Ced-3-like cysteine protease during glucocorticoid-induced apoptosis.
Cancer Res 1997 Jan 01
PMID:Baculovirus P35 inhibits the glucocorticoid-mediated pathway of cell death. 898 38


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