Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abrogation of mitochondrial permeability and induction of reactive oxygen species (ROS) production have been observed in chemical-induced apoptosis; however, the relationship between the mitochondria and intracellular ROS levels in apoptosis is still unclear. In the present study, myricetin (ME) but not its respective glycoside, myricitrin (MI; myricetin-3-O-rhamnose) reduced the viability of human leukemia HL-60 cells via apoptosis, characterized by the occurrence of DNA ladders and hypodiploid cells. Results of Western blotting and caspase activity assays showed that activation of caspases 3 and 9 but not caspases 1, 6 or 8 with cleavage of PARP and D4-GDI proteins is involved in ME-induced apoptosis. A reduction in mitochondrial functions characterized by a decrease in the Bcl-2/Bax protein ratio and translocation of cytochrome c (cyt c) from the mitochondria to the cytosol in accordance with a decrease in mitochondrial membrane potential were observed in ME-treated HL-60 cells. No significant induction of intracellular ROS levels by ME was observed by the DCHF-DA assay, DPPH assay or plasmid digestion assay, and antioxidants including N-acetyl-cysteine (NAC), catalase (CAT), superoxide dismutase (SOD), and tiron (TIR) showed no protective effects on ME-induced apoptosis. A PKC activator, 12-O-tetradecaoylphorbol-13-acetate (TPA) significantly attenuated ME-induced apoptosis via preventing cytochrome c release to the cytosol and maintaining the mitochondrial membrane potential by inhibiting the decrease in the Bcl-2/Bax protein ratio; these effects were blocked by protein kinase C (PKC) inhibitors including GF-109203X, H7, and staurosporin. Removing mitochondria by ethidium bromide (EtBr) treatment reduced the apoptotic effect of ME. Results of SAR studies showed that the presence of OH at C3', C4', and C5' is important for the apoptosis-inducing activities of ME, and that ME induces apoptosis in another leukemia cell line, Jurkat cells, but not in primary human polymorphonuclear (PMN) cells or in murine peritoneal macrophages (PMs). The results of the present study suggest that apoptosis induced by ME occurs through a novel mitochondrion-dependent, ROS-independent pathway; TPA protects cells from ME-induced apoptosis via PKC activation which prevents the occurrence of mitochondrial destruction during apoptosis.
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PMID:Mitochondrial-dependent, reactive oxygen species-independent apoptosis by myricetin: roles of protein kinase C, cytochrome c, and caspase cascade. 1574 3

Previous studies have demonstrated that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a well-known DNA alkylating agent, induces G2/M arrest and apoptotic cell death in several human cancer cell lines. In the present study, we investigated the effects of MNNG on the growth of a U937 human leukemia cell model. The effects of this compound were also tested on cyclooxygenase (COX) activity. Treatment of U937 cells with MNNG resulted in the inhibition of viability and the induction of apoptosis in a concentration-dependent manner, which was associated with a dose-dependent upregulation in pro-apoptotic Bax protein, downregulation of anti-apoptotic Bcl-2 and Bcl-xL proteins, and proteolytic activation of caspase-3 protease. Furthermore, MNNG decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with inactivation of the reporter construct of a COX-2 promoter and decrease in prostaglandin E2 synthesis. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of MNNG.
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PMID:Induction of apoptosis and inhibition of cyclooxygenase-2 expression by N-methyl-N'-nitro-N-nitrosoguanidine in human leukemia cells. 1584 16

Oridonin, an extract from the Chinese herb Rabdosia rubescens, is currently one of the most important traditional Chinese herbal medicines. Recently oridonin has been reported to have anti- tumor effects in a large variety of malignant diseases. In this study, we investigated the apoptotic inducing effect of oridonin in leukemia K562 cells and its mechanism. Cell growth inhibition was measured using a microculture tetrazolium assay, apoptosis was measured by flow cytometry and electron microscopy as well as by DNA fragmentation analysis. Telomerase activity was measured by TRAP-enzyme- linked immunosorbent assay, and the expression of Bcl-2 and Bax proteins was detected by western blot analysis. The results showed that oridonin could inhibit the proliferation and induce apoptosis on leukemia K562 cells remarkably. Telomerase activity as well as Bcl-2 expression was down- regulated, while Bax expression was up-regulated concurrently, when apoptosis ocurred. We therefore conclude that oridonin demonstrated anti-proliferative and apoptosis-inducing effects on K562 cells in vitro, and that changes in bcl-2 and bax protein levels as well as telomerase activity may play an important role in its mechanism of action.
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PMID:Oridonin-induced apoptosis in leukemia K562 cells and its mechanism. 1587 84

Trimidox (3,4,5-trihydroxybenzamidoxime) has been shown to reduce the activity of ribonucleotide reductase accompanied by growth inhibition and the differentiation of mammalian cells. Here we examine the induction of apoptosis by trimidox in several human leukaemia cell lines, focusing on the release of cytochrome c and the activation of caspase proteases in the human B cell line NALM-6. Induction of apoptosis by trimidox (300 microM) was detected in NALM-6, HL-60 (premyelocytic leukaemia cells), MOLT-4 (an acute lymphoblastic leukaemia cells), Jurkat (a T-cell leukaemia cells), U937 (expressing many monocyte-like characteristics), and K562 (erythroleukaemia). NALM-6 was most affected by trimidox among leukaemia cells; therefore, we employed NALM-6 cells in the subsequent experiments. The cells showed a time-dependent increase in DNA damage after trimidox (250 microM) treatment. A significant increase in the amount of cytochrome c release was detected after treatment with trimidox. Bcl-2 and Bax protein expressions were not changed by trimidox. Caspase-3 and -9 were activated by incubation with trimidox, whereas caspase-8 was not. Furthermore, trimidox-induced apoptosis was prevented by a broad-spectrum caspase inhibitor, a caspase-3, and a caspase-9 inhibitor, but not by a caspase-8 inhibitor. Inhibition of c-Jun NH2-terminal kinase (JNK) by SP600125 appreciably protected cells from trimidox-induced apoptosis, but no effect inhibition of p38 mitogen-activated protein kinase (MAPK) by SB203580. In contrast, extracellular signal-regulated kinase (ERK) inhibitors U0126 and PD98059 strongly potentiated the apoptotic effect of trimidox. This report shows that the induction of apoptosis by trimidox occurs through a cytochrome c-dependent pathway, which sequentially activates caspase-3 and caspase-9.
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PMID:Trimidox induces apoptosis via cytochrome c release in NALM-6 human B cell leukaemia cells. 1643 90

Defects in the regulation of programmed cell death play a fundamental role in the development of neoplasia and neurological disorders, both of which are linked to the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infection. We previously showed that the HTLV-1 Tax protein protects from apoptosis induced by serum starvation by preventing cytochrome c release and Bax relocation to mitochondria, two early events in the mitochondrial apoptotic pathway. As a natural extension of these findings, and to better define the action of Tax, in the present study, we investigated the outcome of Tax and two mutants which are inactive in CREB/ATF (M47) or NF-kappaB (M22) pathways, in the control of apoptosis induced by the proapoptotic Bax protein. We found that activation of CREB, rather than NF-kappaB, is a key phenomenon in preventing apoptosis. Furthermore, the importance of CREB activation is strengthened by experiments with CREB mutants, treatment with forskolin, and in situ analysis of P-CREB status in cells transfected with Tax or its nonprotecting M47 mutant. Considered together, these results underscore a primary role of CREB in preventing apoptosis triggered by Bax, and suggest that Tax might act by affecting the phosphorylation state of CREB.
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PMID:Antiapoptotic effect of human T-cell leukemia virus type 1 tax protein correlates with its creb transcriptional activity. 1648 70

Although recent data shows that arsenic trioxide (As2O3) is capable of inducing cell death via cell cycle arrest and apoptosis both in acute promyelocytic leukemia (APL) and in non-APL cells, the mechanisms of As2O3-mediated cell death are not fully understood. In this study, we investigated the in vitro effects of As2O3 on cell growth inhibition and cell death in human T-lymphocytic leukemia and myelodysplastic syndrome (MDS) cell lines. As2O3 significantly inhibited the proliferation of Molt-4 and Mutz-1 cells in dose- and time-dependent manner. Autophagic cell death (programmed cell death type II) and apoptosis (programmed cell death type I) were activated together in leukemia cell lines after exposed to As2O3. Numerous large cytoplasmic inclusions and vacuoles were observed in As2O3-treated cells using electron microscope. Furthermore, 3-methyladenine (an autophagy inhibitor) significantly reduced autophagic cell death and sequentially induced apoptosis. Finally, leukemia cells treated with 4 microM As2O3 showed a considerable up-regulation of Beclin-1 (a Bcl-2-interacting protein) expression, which was independent of transcription of mRNA and required protein synthesis. In addition, Molt-4 cells treated with As2O3 exhibited the down-regulation of Bax protein expression, suggesting that Bax may be involved in accumulating of Beclin-1 and triggering autophagic cell death in As2O3-treated leukemia cells. These results may lead to a better understanding of the mechanism of action of As2O3, and provide a suggestion that As2O3 may be of therapeutic value for the treatment of patients with human T-lymphocytic leukemia and myelodysplastic syndrome.
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PMID:Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. 1688 51

Toona sinensis (T. sinensis), well known in Taiwan as a traditional Chinese medicine, has been shown to exhibit antioxidant effects. In this study, therefore, the ability of T. sinensis to induce apoptosis was studied in cultured human premyelocytic leukemia HL-60 cells. Treatment of the HL-60 cells with a variety of concentrations of the aqueous extracts of T. sinensis (TS extracts) (10-75 microg/ml) and gallic acid (5-10 microg/ml), the natural phenolic components purified from TS extracts, resulted in dose- and time-dependent sequences of events marked by apoptosis, as shown by loss of cell viability and internucleosomal DNA fragmentation. Furthermore, apoptosis in the HL-60 cells was accompanied by the release of cytochrome c, caspase 3 activation and specific proteolytic cleavage of poly (ADP-ribose) polymerase (PARP). This increase in TS extracts- and gallic acid-induced apoptosis was also associated with a reduction in the levels of Bcl-2, a potent cell-death inhibitor, and an increase in those of the Bax protein, which heterodimerizes with and thereby inhibits Bcl-2. Interestingly, TS extracts- and gallic acid-induced dose-dependent reactive oxygen species (ROS) generation in HL-60 cells. We found that catalase significantly decreased TS extracts- or gallic acid-induced cytotoxicity, DNA fragmentation, and ROS production, however, slight reduction was observed with vitamins C and E. Our results indicate that TS extracts- or gallic acid-induced HL-60 apoptotic cell death could be due to the generation of ROS, especially H(2)O(2). The data suggest that T. sinensis exerts antiproliferative action and growth inhibition on HL-60 cells through apoptosis induction, and, therefore, that it may have anticancer properties valuable for application in food and drug products.
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PMID:Toona sinensis extracts induces apoptosis via reactive oxygen species in human premyelocytic leukemia cells. 1694 58

The retrovirus human T-cell lymphotrophic virus type-1 (HTLV-1) causes adult T-cell leukemia (ATL), which remains with no cure. This study evaluates the effects of l-lysine on proliferation and induction of apoptosis using non-cytotoxic concentrations of the test compound against HTLV-1 positive and negative malignant cell lines. The anti-proliferative effect of lysine was established and confirmed by studying the effects of the test compound on the expression of TGF mRNA expression by RT-PCR. To investigate the effect of l-lysine on the induction of apoptosis, DNA flow cytometry analyses was done and the results verified by cell death ELISA. The results indicated that a significant increase in the preG(1) phase and a decrease in the S phase of the cell cycle in all of the ATL cells tested. l-Lysine up-regulated p53, p21, and Bax protein levels and a down-regulation of Bcl-2alpha in all the cell lines tested. l-Lysine was found to exert its effect through the NF-kappaB pathway by inhibiting the p65 subunit specifically. Also l-lysine caused a decrease in the levels MMP-2 and MMP-9 as well as their enzymatic activity.
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PMID:Mechanistic aspects of apoptosis induction by l-lysine in both HTLV-1-positive and -negative cell lines. 1704 5

Using K562 and HL60 cell lines, we have investigated the anti-tumoral activity of d-limonene, a monocyclic monoterpene, in human leukemia cells. Apoptosis was evaluated by Hoechst staining and by the annexin V/propidium iodide binding assay. d-Limonene induced apoptosis in a dose- and time-dependent manner in both cell lines. Our findings and data, demonstrating an increase in Bax protein expression, the release of cytochrome c from mitochondria, and an increase in caspase-9 and cleaved caspase-3, but not caspase-8, after the treatment of d-limonene, all suggest that the mitochondrial death pathway is primarily involved in the development of d-limonene-induced apoptosis.
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PMID:Induction of apoptosis by d-limonene is mediated by a caspase-dependent mitochondrial death pathway in human leukemia cells. 2709 93

Apoptogenic and DNA damaging effects of chelidonine (CHE) and sanguinarine (SAN), two structurally related benzophenanthridine alkaloids isolated from Chelidonium majus L. (Papaveraceae), were compared. Both alkaloids induced apoptosis in human acute T-lymphoblastic leukaemia MT-4 cells. Apoptosis induction by CHE and SAN in these cells was accompanied by caspase-9 and -3 activation and an increase in the pro-apoptotic Bax protein. An elevation in the percentage of MT-4 cells possessing caspase-3 in active form after their treatment with CHE or SAN was in parallel to a corresponding increase in the fraction of apoptotic cells. The involvement of mitochondria in apoptosis induction by both alkaloids was supported by cytochrome C elevation in cytosol, with an accompanying decrease in cytochrome C content in the mitochondrial fraction. At the same time, two alkaloids under study differed drastically in their cell cycle phase-specific effects, since only CHE arrested MT-4 cells in G(2)/M phase. It was shown earlier, that CHE, in contrast to SAN, does not interact directly with DNA. This fact is in line with DNA damaging effects of the alkaloids detected in the COMET assay. Nevertheless, apoptosis-inducing activity of CHE even slightly exceeded that of SAN.
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PMID:Apoptogenic activity of two benzophenanthridine alkaloids from Chelidonium majus L. does not correlate with their DNA damaging effects. 1802 22


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