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)

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity.
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PMID:Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. 968 Mar 69

Since reactive oxygen radicals play an important role in carcinogenesis and other human disease states, antioxidants present in consumable fruits, vegetables, and beverages have received considerable attention as cancer chemopreventive agents. Thus, in order to identify antioxidants in plant extracts, test materials were assessed for potential to scavenge stable 1,2-diphenyl-2-picrylhydrazyl (DPPH) free radicals, reduce TPA-induced free radical formation in cultured HL-60 human leukemia cells, and inhibit responses observed with a xanthine/xanthine oxidase assay system. Approximately 700 plant extracts were evaluated, and 28 were found to be active in the DPPH free radical scavenging assay. Based on secondary analyses performed to assess inhibition of 7,12-dimethylbenz(a)anthracene-induced preneoplastic lesion formation with a mouse mammary organ culture model, Chorizanthe diffusa Benth. (Polygonaceae), Mezoneuron cucullatum Roxb. (Leguminosae), Cerbera manghas L. (Apocynaceae) and Daphniphyllum calycinum Benth. (Daphniphyllaceae) were selected and subjected to bioassay-guided fractionation. 5,7,3',5'-Tetrahydroxy-8,4'-dimethoxyflavonol, 5,8,4'-trihydroxy-7,3'-dimethoxyflavonol, 5,3',4'-trihydroxy-7-methoxyflavonol, and 6,3',4'-trihydroxy-7-methoxyflavonol were identified as active principles from C. diffusa. Piceatannol, trans-resveratrol, apigenin and scirpusin A were found as the active principles of M. cucullatum, olivil, (-)-carinol, and (+)-cycloolivil were active principles from C. manghas, and 5,6,7,4'-tetrahydroxyflavone 3-O-rutinoside and kaempferol 3-O-neohesperidoside were active principles from D. calycinum. Of these substances, the hydroxystilbenes piceatannol and transresveratrol have thus far been shown to inhibit carcinogen-induced preneoplastic lesion formation in the mouse mammary gland organ culture model.
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PMID:Evaluation of the antioxidant potential of natural products. 1049 28

Resveratrol, a natural product present in wine, has recently been shown to inhibit the growth of a number of cancer cell lines in vitro. In the current study, we have demonstrated that resveratrol inhibits the growth of THP-1 human monocytic leukaemia cells in a dose-dependent manner with a median effective dose of 12 microM. It did not induce differentiation of THP-1 cells and had no toxic effect on THP-1 cells that had been induced to differentiate into monocytes/macrophages by phorbol myristate acetate. A significant fraction of resveratrol-treated cells underwent apoptosis as judged by flow cytometric analysis of DNA content, DNA fragmentation and caspase-specific cleavage of poly(ADP-ribosyl) polymerase. Resveratrol treatment had no effect on the expression of Fas receptor or Fas ligand (FasL) in THP-1 cells, nor did it induce clustering of Fas receptors. In addition, THP-1 cells were resistant to activating anti-Fas antibody, and neutralizing anti-Fas and/or anti-FasL antibodies had no protective effect against resveratrol-induced inhibition of THP-1 cell growth. The effect of resveratrol on THP-1 cells was reversible after its removal from the culture medium. These results suggest that (1) resveratrol inhibits the growth of THP-1 cells, at least in part, by inducing apoptosis, (2) resveratrol-induced apoptosis of THP-1 cells is independent of the Fas/FasL signalling pathway and (3) resveratrol does not induce differentation of THP-1 cells and has no toxic effect on differentiated THP-1 cells. Thus, resveratrol may be a potential chemotherapeutic agent for the control of acute monocytic leukaemia.
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PMID:Resveratrol induces Fas signalling-independent apoptosis in THP-1 human monocytic leukaemia cells. 1084 32

Resveratrol, a plant antibiotic, has been found to have anticancer activity and was recently reported to induce apoptosis in the myeloid leukemia line HL60 by the CD95-CD95 ligand pathway. However, many acute lymphoblastic leukemias (ALLs), particularly of B-lineage, are resistant to CD95-mediated apoptosis. Using leukemia lines derived from patients with pro-B t(4;11), pre-B, and T-cell ALL, we show in this report that resveratrol induces extensive apoptotic cell death not only in CD95-sensitive leukemia lines, but also in B-lineage leukemic cells that are resistant to CD95-signaling. Multiple dose treatments of the leukemic cells with 50 microM resveratrol resulted in >/=80% cell death with no statistically significant cytotoxicity against normal peripheral blood mononuclear cells under identical conditions. Resveratrol treatment did not increase CD95 expression or trigger sensitivity to CD95-mediated apoptosis in the ALL lines. Inhibition of CD95-signaling with a CD95-specific antagonistic antibody indicated that CD95-CD95 ligand interactions were not involved in initiating resveratrol-induced apoptosis. However, in each ALL line, resveratrol induced progressive loss of mitochondrial membrane potential as measured by the dual emission pattern of the mitochondria-selective dye JC-1. The broad spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone failed to block the depolarization of mitochondrial membranes induced by resveratrol, further indicating that resveratrol action was independent of upstream caspase-8 activation via receptor ligation. However, increases in caspase-9 activity ranged from 4- to 9-fold in the eight cell lines after treatment with resveratrol. Taken together, these results point to a general mechanism of apoptosis induction by resveratrol in ALL cells that involves a mitochondria/caspase-9-specific pathway for the activation of the caspase cascade and is independent of CD95-signaling.
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PMID:Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. 1140 44

Resveratrol, a naturally occurring plant antibiotic has been the focus of a number of studies investigating its biological attributes, which include anti-oxidant activity, anti-platelet aggregation effect, anti-atherogenic property, estrogen-like growth promoting effect, growth inhibiting activity, immunomodulation, and chemoprevention. More recently, since the first report on the apoptosis inducing activity of resveratrol in human cancer cells, the interest in this molecule as a potential chemotherapy agent has significantly intensified. Not only has its role as an anti-cancer agent been corroborated, but the precise mechanism(s) of the anti-cancer activity of resveratrol is/are being elucidated. Our group has been active in studying the cross talk between the caspase family of proteases and mitochondria, in drug-induced apoptosis. In this regard, we have shown that the cancer preventive activity of resveratrol could be attributed to its ability to trigger apoptosis in human leukemia and breast carcinoma cells. The cytotoxicity of resveratrol is restricted against these transformed cell types due to its ability to selectively upregulate CD95-CD95L interaction on the tumor cell surface, unlike normal peripheral blood cells. Despite the involvement of the CD95 signaling pathway, apoptosis induced by resveratrol is not accompanied by robust caspase 8 activation, but involves mitochondrial release of cytochrome C and downstream activation of caspases 9 and 3. We also extrapolate these in vitro findings in a murine model of carcinogensis, and demonstrate in vivo induction of apoptosis in mouse skin papillomas. These findings highlight the chemotherapeutic potential of this polyphenolic compound.
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PMID:Resveratrol--from the bottle to the bedside? 1142 22

Trans-resveratrol was analysed for its apoptotic and growth inhibitory activity in human B-cell lines derived from chronic B-cell malignancies (WSU-CLL and ESKOL), and in leukaemic lymphocytes from patients with B-cell chronic lymphocytic leukaemia (B-CLL). Resveratrol displayed antiproliferative activity on both B-cell lines, as estimated by the decrease in cell recovery and inhibition of thymidine uptake. Furthermore, resveratrol induced apoptosis in the two cell lines as well as in B-CLL patients' cells, as evidenced by the increase in annexin V binding, caspase activation, DNA fragmentation and decrease of the mitochondrial transmembrane potential DeltaPsim. We previously reported that nitric oxide (NO), endogenously released by an iNO synthase (iNOS) spontaneously expressed in these leukaemic cells, contributed to their resistance towards apoptosis. We show here that resveratrol inhibited both iNOS protein expression and in situ NO release in WSU-CLL, ESKOL and B-CLL patients'cells. In addition, Bcl-2 expression was also inhibited by resveratrol. Thus, downregulation of the two anti-apoptotic proteins iNOS and Bcl-2 can contribute to the apoptotic effects of resveratrol in leukaemic B cells from chronic leukaemia. Our data suggest that this drug is of potential interest for the therapy of B-CLL.
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PMID:Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia. 1206 Jan 19

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenol found in grapes and grape wine, has been reported to exhibit cardioprotective and chemopreventive activity against chemical carcinogenesis. It has also been shown to have growth inhibitory activity toward solid tumors in vivo. However, the antitumor activity of resveratrol against hematologic tumors in vivo has not been examined. In this study, the antileukemic activity of resveratrol in vitro and in vivo was examined using a mouse myeloid leukemia cell line (32Dp210). Treatment of 32Dp210 leukemia cells with resveratrol at micromolar concentrations (25-50 micromol/L) significantly and irreversibly inhibited their clonal growth in vitro. The clonal growth inhibition by resveratrol was associated with extensive cell death and an increase in hypodiploid (sub-G1) cells. Resveratol caused internucleosomal DNA fragmentation, suggesting apoptosis as the mode of cell death in 32Dp210 cells. DNA fragmentation was associated with activation of caspase-3, because cleavage of procaspase-3 was detected in resveratrol-treated cells. Although 32Dp210 cells treated with resveratrol in vitro did not produce leukemia in vivo, only a weak antileukemic effect of resveratrol was observed when administered orally. At doses of 8 mg or 40 mg/kg body daily, five times/wk, resveratrol did not affect the survival of mice injected with leukemia cells. Weak potential antileukemic activity of resveratrol was suggested only at a dose of 80 mg/kg body (2 survivors of 14 mice treated). Thus, despite strong antiproliferative and proapoptotic activities of resveratrol against 32Dp210 cells in vitro, a potential antileukemia effect in vivo, if present, occurs only in a small fraction of mice.
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PMID:Disparate in vitro and in vivo antileukemic effects of resveratrol, a natural polyphenolic compound found in grapes. 1209 96

Resveratrol is a phytoalexin naturally present in fruits, medicinal plants and wines. It has a diversity of biological activities. While its role in the protection against coronary heart disease (CHD) in people with moderate wine consumption, remains unclear, resveratrol preferentially inhibits the growth of leukemia cells in culture. Potential mechanisms for its anti-leukemia effect include induction of leukemia cell differentiation, apoptosis, and cell cycle arrest at S-phase; and inhibition of DNA synthesis by inhibiting ribonucleotide reductase or DNA polymerase. Preliminary results suggest that resveratrol also inhibits the viability of freshly isolated leukemia cells, especially promyelocytic leukemia cells. Because of its low in vivo toxicity, resveratrol deserves further investigation as an anti-leukemia agent.
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PMID:Anti-leukemia effect of resveratrol. 1214 9

Resveratrol, an edible polyphenolic stilbene, has been reported to possess substantial antileukemic activities in different leukemia cell lines. We investigated whether resveratrol is active against fresh acute myeloid leukemia (AML) cells and its mechanism of action. Because interleukin 1beta(IL-1beta) plays a key role in proliferation of AML cells, we first tested the effect of resveratrol on the AML cell lines OCIM2 and OCI/AML3, both of which produce IL-1beta and proliferate in response to it. Resveratrol inhibited proliferation of both cell lines in a dose-dependent fashion (5-75 microM) by arresting the cells at S phase, thus preventing their progression through the cell cycle; IL-1beta partially reversed this inhibitory effect. Resveratrol significantly reduced production of IL-1beta in OCIM2 cells. It also suppressed the IL-1beta-induced activation of transcription factor nuclear factor kappaB (NF-kappaB), which modulates an array of signals controlling cellular survival, proliferation, and cytokine production. Indeed, incubation of OCIM2 cells with resveratrol resulted in apoptotic cell death. Because caspase inhibitors Ac-DEVD-CHO or z-DEVD-FMK partially reversed the antiproliferative effect of resveratrol, we tested its effect on the caspase pathway and found that resveratrol induced the activation of the cysteine protease caspase 3 and subsequent cleavage of the DNA repair enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase. Finally, resveratrol suppressed colony-forming cell proliferation of fresh AML marrow cells from 5 patients with newly diagnosed AML in a dose-dependent fashion. Taken together, our data showing that resveratrol is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.
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PMID:Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. 1268 43

Investigation has been conducted to delineate the action of some phenolic compounds of natural origin in four human tumor cell lines: acute myeloblastic leukemia (HL-60), chronic myelogenic leukemia (K-562), breast adenocarcinoma (MCF-7) and cervical epithelial carcinoma (HeLa). In cells grown in appropriate media the phenolics curcumin, yakuchinone B, resveratrol and capsaicin exhibited growth inhibition as assessed by trypan blue dye exclusion. It was evident from the results of the MTT reduction assay and [(3)H]thymidine incorporation into nuclear DNA that the phenolics were cytotoxic and inhibited cell proliferation. Dose response studies indicated curcumin to be most cytotoxic towards HL-60, K-562 and MCF-7 but did not show much activity in HeLa cells. On the other hand, yakuchinone B, although less active than curcumin, displayed cytotoxicity towards all four cell lines. Resveratrol was cytotoxic only in leukemic cells, while capsaicin was marginally cytotoxic. All these phenolics did not elicit any cytotoxic activity as judged by the above parameters towards lymphocytes purified from normal human blood. When cells treated with phenolics were stained with propidium iodide and examined under a fluorescent microscope, characteristic apoptotic features such as chromatin condensation and nuclear fragmentation were observed. Scoring of cells with apoptotic and non-apoptotic features showed positive correlation of apoptotic index with dose of phenolic, and fragmented DNA extracted free of genomic DNA displayed on gel electrophoresis a typical ladder pattern. These phenolics which have human exposure are known cancer chemopreventive agents and their action as inducers of apoptosis in tumor cells suggest their potential use in a strategy for cancer control.
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PMID:Induction of Apoptosis in Tumor Cells by Natural Phenolic Compounds. 1271 10


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