Mistletoe lectin activates caspase-8/FLICE independently of death receptor signaling and enhances anticancer drug-induced apoptosis.
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Mistletoe lectin I (ML-I) is a major active component in plant extracts of Viscum album that is increasingly used in adjuvant cancer therapy. ML-I exerts potent immunomodulating and cytotoxic effects, although its mechanism of action is largely unknown. We show that treatment of leukemic T- and B-cell lines with ML-I induced apoptosis, which required the prior activation of proteases of the caspase family. The involvement of caspases is demonstrated because (a) a peptide caspase inhibitor almost completely prevented ML-I-induced cell death and (b) proteolytic activation of caspase-8, caspase-9, and caspase-3 was observed. Because caspase-8 has been implicated as a regulator of apoptosis mediated by death receptors, we further investigated a potential receptor involvement in ML-I-induced effects. Cell death triggered by ML-I was neither attenuated in cell clones resistant to CD95 nor in cells that were rendered refractory to other death receptors by overexpressing a dominant-negative FADD mutant. In contrast, ML-I triggered a receptor-independent mitochondria-controlled apoptotic pathway because it rapidly induced the release of cytochrome c into the cytosol. Because ML-I was also observed to enhance the cytotoxic effect of chemotherapeutic drugs, these data may provide a molecular basis for clinical trials using MLs in anticancer therapy. (+info)
Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and gamma-radiation downstream from caspase-8 activation.
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The death receptor CD95 (APO-1/Fas), the anticancer drug etoposide, and gamma-radiation induce apoptosis in the human T cell line Jurkat. Variant clones selected for resistance to CD95-induced apoptosis proved cross-resistant to etoposide- and radiation-induced apoptosis, suggesting that the apoptosis pathways induced by these distinct stimuli have critical component(s) in common. The pathways do not converge at the level of CD95 ligation or caspase-8 signaling. Whereas caspase-8 function was required for CD95-mediated cytochrome c release, effector caspase activation, and apoptosis, these responses were unaffected in etoposide-treated and irradiated cells when caspase-8 was inhibited by FLIPL. Both effector caspase processing and cytochrome c release were inhibited in the resistant variant cells as well as in Bcl-2 transfectants, suggesting that, in Jurkat cells, the apoptosis signaling pathways activated by CD95, etoposide, and gamma-radiation are under common mitochondrial control. All three stimuli induced ceramide production in wild-type cells, but not in resistant variant cells. Exogenous ceramide bypassed apoptosis resistance in the variant cells, but not in Bcl-2-transfected cells, suggesting that apoptosis signaling induced by CD95, etoposide, and gamma-radiation is subject to common regulation at a level different from that targeted by Bcl-2. (+info)
Inhibition of harringtonine-induced apoptosis by tetradecanoylphorbol acetate in human leukemia HL-60 cells.
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AIM: To study the changes of the apoptosis induced by camptothecin (Cam) or harringtonine (Har) in human leukemia HL-60 cells after the cells were preincubated with tetradecanoylphorbol acetate (TA). METHODS: Chromatin condensation observation, flow cytometry, DNA agarose gel electrophoresis, and Dot blot hybridization. RESULTS: After the HL-60 cells were preincubated with TA 200 nmol.L-1 for 6 h, the apoptosis induced by Har 0.1 mg.L-1 for 3 h was drastically inhibited, and the apoptosis by Cam 0.2 mg.L-1 for 3 h was partly inhibited. On the other hand, the expression level of c-myc gene in HL-60 cells decreased apparently after the preincubation of TA. CONCLUSION: TA preincubation inhibited the apoptosis induced by Har obviously or by Cam partly in human leukemia HL-60 cells, and the expression of c-myc gene decreased drastically in the preincubated cells, which might result in the inhibition of apoptosis. (+info)
The ATM protein is required for sustained activation of NF-kappaB following DNA damage.
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Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kappaB. It is activated by various stress situations, including oxidative stress, and by DNA-damaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kappaB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kappaB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NF-kappaB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation. (+info)
Modulating activity of indomethacin to vincristine cytotoxicity in various human carcinoma cells.
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The modulating activity of indomethacin to vincristine (VCR) was investigated in thirty human pulmonary carcinoma cell lines (adenocarcinoma 9, large cell carcinoma 9, squamous cell carcinoma 6, small cell carcinoma 6) and five other cell lines (colon carcinoma 2, melanoma 1, teratocarcinoma 1, thymoma 1). The survival of these cell lines treated with VCR with or without indomethacin (2 microg/ml) for 72 hours were examined using MTT assay, and IC50 values were calculated. When the cutoff level of potent combined effect in clinical use was set at 2-fold increase of sensitivity, the positive rate was 100% for adenocarcinomas and large cell carcinomas, 25% for squamous cell carcinomas, 33% for small cell carcinomas. Mean modulating index was 2.91 in adenocarcinomas, 1.92 in squamous cell carcinomas, 3.06 in large cell carcinomas and 1.67 in small cell carcinomas. Of the cell lines of other tumors, three cell lines (colon carcinoma 1, melanoma 1, teratocarcinoma 1) showed the potent combined effect of VCR and indomethacin, while indomethacin was not effective in modulating activity to VCR in a thymoma cell line and fibroblast cells. In conclusion, it is considered that modulating activity of indomethacin for VCR is a general effect for various human cancer cells, and combined use with VCR and indomethacin may be a useful modulation therapy for the advanced lung cancer. (+info)
Irinotecan therapy in adults with recurrent or progressive malignant glioma.
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PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma. PATIENTS AND METHODS: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients. RESULTS: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment. CONCLUSION: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance. (+info)
Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing.
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Betulinic acid (BA), a pentacyclic triterpene, is an experimental cytotoxic agent for malignant melanoma. Here, we show that BA triggers apoptosis in five human glioma cell lines. BA-induced apoptosis requires new protein, but not RNA, synthesis, is independent of p53, and results in p21 protein accumulation in the absence of a cell cycle arrest. BA-induced apoptosis involves the activation of caspases that cleave poly(ADP ribose)polymerase. Interactions of death ligand/receptor pairs of the CD95/CD95 ligand family do not mediate BA-induced caspase activation. BA enhances the levels of BAX and BCL-2 proteins but does not alter the levels of BCL-xS or BCL-xL. Ectopic expression of BCL-2 prevents BA-induced caspase activation, DNA fragmentation, and cell death. Furthermore, BA induces the formation of reactive oxygen species that are essential for BA-triggered cell death. The generation of reactive oxygen species is blocked by BCL-2 and requires new protein synthesis but is unaffected by caspase inhibitors, suggesting that BA toxicity sequentially involves new protein synthesis, formation of reactive oxygen species, and activation of crm-A-insensitive caspases. (+info)
Monotherapy of metastatic breast cancer: a review of newer agents.
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PURPOSE: New agents for the palliative treatment of metastatic breast cancer have emerged in the 1990s. This review summarizes the response rates of these agents with an emphasis on recent findings, such as presentations from the 1998 Meeting of the American Society of Clinical Oncology. METHODS: The English medical literature was reviewed to identify clinical trials involving monotherapy for the treatment of metastatic breast cancer. Three agents--paclitaxel, vinorelbine, and docetaxel--are emphasized because their databases are extensive enough to allow interesting comparisons. Liposomal-encapsulated anthracyclines, losoxantrone, gemcitabine, oral surrogates of continuous-infusion fluorouracil, raltitrexed, LY 231514, edatrexate, topoisomerase I inhibitors, and trastuzumab are reviewed briefly. RESULTS: Many of the new agents produce response rates approaching or even surpassing those achievable with doxorubicin monotherapy. Compared with older agents, some new agents have improved or at least different safety profiles, and some are easier to administer. DISCUSSION AND CONCLUSIONS: The new agents offer useful therapeutic options that make them suitable for combining with each other and with older agents, which could result in more effective regimens for metastatic disease, and, ultimately, primary disease in the adjuvant setting. The chemotherapeutic paradigms governing the management of breast cancer for the past three decades are likely to change as we move into the 21st century. (+info)