Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic trioxide (As2O3) has been reported to induce apoptosis in human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines and fresh adult T-cell leukemia (ATL) cells and to induce G1 phase accumulation in HTLV-I infected T-cell lines. The present study aimed to clarify the pathway of As2O3-induced apoptosis in HTLV-I infected T-cell lines, MT-1 and MT-2, and fresh ATL cells separated from peripheral blood of patients with acute or chronic type ATL. Cells were treated up to 72 h at clinically tolerable concentrations of As2O3 (1-2 micromol/l) shown to be safe in patients with acute promyelocytic leukemia (APL). Activation of caspases 3, 8, and 9, loss of mitochondrial transmembrane potential and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) were observed during As2O3 treatment. Furthermore, prior exposure to a broad-spectrum caspase inhibitor blocked As2O3-induced apoptosis but not G1 phase accumulation. While pre-treatment with a CD95 receptor-blocking antibody (Ab) or a TNF-alpha neutralizing Ab did not show such inhibitions in these cells. In conclusion, As2O3 induces apoptosis in HTLV-I infected T-cell lines and fresh ATL cells through CD95 or TNF-alpha receptor independent caspase activation.
Leuk Lymphoma 2002 May
PMID:Arsenic trioxide induces apoptosis in HTLV-I infected T-cell lines and fresh adult T-cell leukemia cells through CD95 or tumor necrosis factor alpha receptor independent caspase activation. 1214 93

The pyrimidine analogue Ara-C and the purine analogues fludarabine and cladribine (2-CdA) are essential compounds in the treatment of acute myeloid leukemia (AML). Inhibition of cell proliferation and induction of apoptosis are the major mechanisms of cytotoxic agents to cause tumor cell death. Therefore, we studied whether Ara-C in combination with the purine analogues exerts synergistic or antagonistic effects on cell proliferation, phosphatidylserine exposure and disruption of mitochondrial membrane potential (MMP) in the AML cell lines HL60 and HEL. Furthermore, effects of the combination of Ara-C with bendamustine, a new bifunctional agent with alkylating activity and a purine nucleus, was investigated. Assessment by combination index analysis showed that Ara-C combined with fludarabine or bendamustine exhibited additive to antagonistic effects on inhibition of cell proliferation, induction of apoptosis as well as on disruption of mitochondrial membrane potential, independent of a simultaneous or consecutive (purine analogues before Ara-C) incubation schedule. In contrast, the combination of Ara-C with 2-CdA exclusively yielded synergistic effects. While inducing IC50 levels of apoptosis neither the antagonistic nor the synergistic drug combinations caused a specific expression pattern of apoptosis-associated proteins such as the pro- or antiapoptotic Bcl-2 family members, executioner caspases, IAPs (inhibitor of apoptosis proteins), proapoptotic Par-4, PARP, or p53. In conclusion, we here demonstrate that the in vitro efficacy of drug combinations containing Ara-C and purine analogues depends on the purine analogue applied, whereas incubation schedules or escalating dosages do not contribute to the synergistic effects.
Leuk Lymphoma 2003 Jan
PMID:In AML cell lines Ara-C combined with purine analogues is able to exert synergistic as well as antagonistic effects on proliferation, apoptosis and disruption of mitochondrial membrane potential. 1269 Nov 59

Induction of apoptosis contributes to the cytotoxic action of the intravenously applicable alkylphosphocholine erucylphosphocholine (ErPC). To define molecular requirements for ErPC-induced apoptosis, activation of caspases-8, -9 and -3 and cleavage of the caspase-3 substrates PARP and ICAD were tested in normal Jurkat T cells, Jurkat cells resistant to death receptor (CD95 or TNFalpha-related apoptosis inducing ligand (TRAIL)-induced apoptosis, Jurkat cells lacking caspase-8 or Fas-associated death domain (FADD) Jurkat cells expressing a dominant-negative caspase-9 or overexpressing Bcl-2 as well as BJAB B-lymphoma cells expressing a dominant-negative FADD (FADD-DN). ErPC induced a time- and dose-dependent apoptotic cell death in Jurkat and BJAB cells, which was characterized by breakdown of the phosphatidylserine asymmetry, depolarization of the mitochondrial membrane potential, release of cytochrome c, activation of caspases-9, -8 and -3, cleavage of PARP and ICAD, as well as chromatin condensation. ErPC-induced apoptosis was independent from CD95-receptor signaling and FADD since CD95- and TRAIL-resistant, caspase-8- and FADD-negative Jurkat cells, as well as BJAB cells expressing FADD-DN were sensitive to ErPC-induced apoptosis. In contrast, inhibition of caspase-9 and overexpression of Bcl-2 significantly reduced ErPC-induced caspase activation and apoptosis. Thus, ErPC triggers apoptosis via a Bcl-2-dependent mitochondrial but death receptor-independent pathway.
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PMID:Intracellular mediators of erucylphosphocholine-induced apoptosis. 1273 Jun 76

The bitter acids of hops (Humulus lupulus L.) mainly consist of alpha-acids, beta-acids, and their oxidation products that contribute the unique aroma of the beer beverage. Hop bitter acids displayed a strong growth inhibitory effect against human leukemia HL-60 cells, with an estimated IC(50) value of 8.67 microg/mL, but were less effective against human histolytic lymphoma U937 cells. Induction of apoptosis was confirmed in HL-60 cells by DNA fragmentation and the appearance of a sub-G1 DNA peak, which were preceded by dissipation of mitochondrial membrane potential, cytochrome c release, and subsequent induction of pro-caspase-9 and -3 processing. Cleavages of PARP and DFF-45 were accompanied with activation of caspase-9 and -3 triggered by hop bitter acids in HL-60 cells. The change in the expression of Bcl-2, Bcl-X(L), and Bax in response to hop bitter acids was studied, and the Bcl-2 protein level slightly decreased; however, the Bcl-X(L) protein level was obviously decreased, whereas the Bax protein level was dramatically increased, indicating that the control of Bcl-2 family proteins by hop bitter acids might participate in the disruption of mitochondrial integrity. In addition, the results showed that hop bitter acids promoted the up-regulation of Fas and FasL prior to the processing and activation of pro-caspase-8 and cleavage of Bid, suggesting the involvement of a Fas-mediated pathway in hop bitter acids-induced cells. Taken together, these findings suggest that a certain intimate link might exist between receptor- and mitochondria-mediated death signalings that committed to cell death induced by hop bitter acids. The induction of apoptosis by hop bitter acids may offer a pivotal mechanism for their chemopreventive action.
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PMID:Mechanisms of cancer chemoprevention by hop bitter acids (beer aroma) through induction of apoptosis mediated by Fas and caspase cascades. 1470 13

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

Studies to investigate signal transduction pathways that support viability and prevent apoptosis of chronic lymphocytic leukemia cells (CLL) were initiated as a result of microarray cDNA analyses which revealed expression of genes whose products regulate cell cycle progression. Immunoblots revealed translation of several genes including caspases, cyclin D1, and the PI3-kinase dependent, survival kinase, Akt. Akt was found to be activated. Inhibition of PI3-kinase with specific inhibitor, LY294002, led to the induction of apoptosis that was caspase 8 dependent, but independent of Akt as LY294002 did not depress a high basal level of Akt activity found in CLL cells. Phosphorylation of Akt was maintained, enzymatic activity undiminished, and phosphorylation of substrates sustained. Caspases, however were activated, PARP cleaved and DNA fragmented. Caspase inhibitors revealed that initiator caspase 8 was required for classic apoptosis when PI3-kinase was inhibited, and specific activity assays demonstrated its early activation. GSK-3beta a kinase regulated via PI3-kinase dependent, down-stream kinases, was responsible for regulating cyclin D1 levels in CLL cells, but neither GSK-3beta nor calpain was responsible for induction of apoptosis, or activation of executioner caspase 3, following LY294002 treatment. PI3-kinase mediated protection against caspase activation in CLL B-cells therefore is not mediated through classic Akt survival pathways. The data further support the hypothesis that signal transducing, membrane associated receptors triggered by extrinsic factors, maintain CLL leukemic B-cell survival in vivo by preventing caspase activation.
Leuk Lymphoma 2004 Aug
PMID:PI3-kinase regulates survival of chronic lymphocytic leukemia B-cells by preventing caspase 8 activation. 1537 Feb 2

We previously demonstrated that intravenous or intra-cerebral administration of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors increases the antitumor activity of temozolomide (TMZ), an oral anticancer drug used for the treatment of malignant melanoma and primary or secondary brain tumors. Since the oral route has a number of advantages in terms of safety and convenience with respect to intravenous injection, in this study we tested whether administration per os of the novel PARP-1 inhibitor GPI 15427 allows sufficient absorption of the compound and achievement of brain concentrations capable of enhancing the efficacy of TMZ against tumors growing at the CNS. Pharmacokinetics analysis of GPI 15427 levels in plasma and brain was assessed in Sprague-Dawley rats after oral dosing, by liquid chromatography and tandem mass spectrometry. Antitumor activity of oral GPI 15427 in association with TMZ was evaluated in BD2F1 mice injected intracranially with B16 melanoma or L5178Y lymphoma. Pharmacokinetics studies revealed that GPI 15427 possesses a substantial oral bioavailability (plasma Cmax after a single dose of 40 mg/kg: 1041+/-516 ng/ml). Moreover, the brain levels and brain/plasma ratios of GPI 15427 (3.37 at 0.5 h and 3.19 at 1 h) indicated that the compound readily penetrates the blood-brain barrier. GPI 15427 (10 or 40 mg/kg/per os) was then administered for five days, 1 h before TMZ (100 mg/kg/i.p.), to tumor-bearing mice. The results indicated that GPI 15427+TMZ was well tolerated and significantly increased life-span of the animals with respect to TMZ. In conclusion, PARP-1 inhibitor GPI 15427 is efficacious as chemosensitizer for the treatment of tumors located at the CNS site when it is administered by oral route.
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PMID:Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors. 1564 26

Podophyllum hexandrum Royale (Himalayan mayapple), a high-altitude Himalayan plant, has been shown to provide over 80% whole-body radioprotection in mice. To investigate the radioprotective potential of P. hexandrum at the molecular level, expression patterns of various proteins associated with apoptosis were studied in the spleen of male Swiss albino strain A mice by immunoblotting. Treatment with P. hexandrum [200 mg/kg of body weight; an ethanolic 50% (w/v) extract delivered intraperitoneally] 2 h before irradiation resulted in MAPKAP (mitogen-activated protein kinase-activated protein) kinase-2 activation along with HSF-1 (heat-shock transcription factor-1), leading to up-regulation of HSP-70 (heat-shock protein-70) as compared with sham-irradiated (10 Gy) mice. Strong inhibition of AIF (apoptosis-inducing factor) expression was observed in the mice treated with P. hexandrum 2 h before irradiation as compared with the sham-irradiated group. Inhibition in the translocation of free NF-kappaB (nuclear factor kappaB) from cytoplasm to nucleus was observed upon P. hexandrum pretreatment 2 h before irradiation when compared with radiation-treated mice. P. hexandrum pre-treatment (2 h before irradiation) resulted in inhibition of NF-kappaB translocation, and the expression of tumour suppressor protein p53 was observed to be down-regulated as compared with sham-irradiated control. An increase in the expression of proteins responsible for cell proliferation [Bcl-2 (B-cell chronic lymphocytic lymphoma 2), Ras-GAP (Ras-GTPase-activating protein) and PCNA (proliferating cell nuclear antigen)] was observed in the P. hexandrum-pretreated irradiated mice as compared with sham-irradiated controls. Caspase 3 activation resulted PARP [poly(ADP-ribose) DNA polymerase] cleavage, and DNA degradation was strongly inhibited in the mice treated with P. hexandrm (+/-irradiation) as compared with the mice treated with radiation (+/-heat shock). The present study thus clearly demonstrated that P. hexandrum extract provides protection from gamma-radiation by the modulation of expression of proteins associated with cell death.
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PMID:Podophyllum hexandrum (Himalayan mayapple) extract provides radioprotection by modulating the expression of proteins associated with apoptosis. 1576 43

More than half of anaplastic large-cell lymphoma (ALCL) are associated with chromosomal translocation t(2;5)(p23;q35) that leads to the expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncoprotein. NPM-ALK activates the antiapoptotic phosphatidylinositol-3 kinase/Akt (PI3K/Akt) signaling pathway, which plays a critical role in cell survival and apoptosis. Inhibition of the PI3K/Akt pathway has been considered as a therapeutic target for cancer where PI3K/Akt activation is a causative factor. Genistein, a natural isoflavonoid found in soy products, has been shown to inhibit cell growth and induce apoptosis in a wide variety of cell lines. Here, we demonstrated that treatment of two t(2;5) ALCL cell lines, SUDHL-1 and Karpas299, with genistein induced apoptosis in a time- and dose-dependent manner. Concurrently, these cells exhibited a decrease in Akt protein levels and subsequent downregulation of Akt activity (Akt phosphorylation). Furthermore, genistein treatment induced mitochondrial membrane potential change, caspase-3 activation and PARP cleavage. From these results, we conclude that inhibition of the Akt signaling pathway and induction of apoptosis by genistein could be used as a new treatment modality for the prevention and/or treatment of t(2;5) ALCL and other hematopoietic malignancies.
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PMID:Genistein-induced apoptosis via Akt signaling pathway in anaplastic large-cell lymphoma. 1588 21

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is the only non-steroidal anti-inflammatory drug so far which has been approved by the FDA for adjuvant treatment of patients with familial adenomatous polyposis. The molecular mechanism responsible for the anti-cancer effects of celecoxib is not fully understood. There is little data on the potential role of COX-2 in lymphoma pathogenesis. In view of the reported induction of apoptosis in cancer cells by cyclooxygenase-2 inhibitors, the present study is undertaken to test the effect of celecoxib on human chronic myeloid leukemia cell line, K562 and other hematopoietic cancer cell lines like Jurkat (human T lymphocytes), HL60 (human promyelocytic leukemia) and U937 (human macrophage). Treatment of these cells with celecoxib (10-100 microM) dose-dependently, reduced cell growth with arrest of the cell cycle at G0/G1 phase and induction of apoptosis. Further mechanism of apoptosis induction was elucidated in detail in K562 cell line. Apoptosis was mediated by release of cytochrome c into the cytoplasm and cleavage of poly (ADP-ribose) polymerase-1 (PARP-1). This was followed by DNA fragmentation. The level of anti-apoptotic protein Bcl-2 was decreased without any change in the pro-apoptotic Bax. Celecoxib also inhibited NF-kB activation. Celecoxib thus potentiates apoptosis as shown by MTT assay, cytochrome c leakage, PARP cleavage, DNA fragmentation, Bcl-2 downregulation and possibly by inhibiting NF-kB activation.
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PMID:Anti-proliferative and apoptotic effects of celecoxib on human chronic myeloid leukemia in vitro. 1591 Oct 99


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