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  • 1
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    Online Resource
    Glutathione Depletion Enhances Arsenic Trioxide-Induced Apoptosis in Lymphoma Cells through Mitochondrial and Caspase-Independent Mechanisms.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2708-2708
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2708-2708
    Abstract: Abstract 2708 Poster Board II-684 Introduction: Arsenic trioxide (ATO) induces apoptosis in cancer through several mechanisms including modulation of the redox system and targeting the BCL-2 family and mitochondria, resulting in cytochrome c release and activation of caspases. However, the mechanisms of arsenic-induced cell death in lymphoma remain to be elucidated, while methods to enhance ATO-related apoptosis have not been fully explored. In the present study, we evaluated the cytotoxic activity and pathways of cell death induced by ATO alone and in combination with a glutathione (GSH)-depleting agent in non-Hodgkin lymphoma (NHL) cell lines and primary cells from patients with lymphoma. We hypothesized that depletion of GSH would enhance ATO induced apoptosis through mitochondrial and caspase-mediated pathways. Methods: We treated Ramos (Burkitt lymphoma), HF1 (follicular lymphoma), and SUDHL4 (diffuse large B-cell lymphoma) NHL cell lines, and primary follicular lymphoma and CLL/SLL cells with increasing concentrations (10–100μM) of ATO for 24–72 hours (hrs). Apoptosis was determined by Annexin V-Propidium iodide staining followed by flow cytometry and Z-VAD-FMK was used as a pan-caspase inhibitor. ROS was measured by H2DCFDA staining followed by flow cytometry. We further studied the mechanism of apoptosis by measuring alteration in mitochondrial membrane potential (MMP), Bax translocation, and caspase and PARP activation. In addition, we treated wild type and Bax−/−/Bak−/− double knockout mouse endothelial fibroblasts (MEFS) with ATO or ATO/BSO and determined apoptosis and mitochondrial membrane potential compared with MEF wild type (MEF-wt). Results: Treatment of cells with ATO resulted in dose- and time-dependent apoptosis, although high concentrations were necessary for effect (ED50 〉 10–20μM). ATO treatment redistributed Bax from the cytosol to mitochondria and there were significant changes in MMP, as well as increased PARP, cleaved caspse-3 and -9, while BID was downregulated. Furthermore, ATO-induced apoptosis was caspase-dependent. Addition of the GSH-depleting agent, buthionine sulfoximine (BSO), to ATO induced strong synergistic cell death (combination indices 〈 0.1 in all cell lines), resulting in apoptosis that was ROS-related, but mitochondrial- and caspase-independent. Using immortalized wild-type MEFS and Bax−/−Bak−/− double knockouts, ATO-induced alteration in MMP and apoptosis that was Bax-dependent (see figure below), while targeted disruption of the Bax/Bak genes had no enhancing effects on ATO/BSO-induced MMP or apoptosis. Interestingly, ATO alone induced appreciable apoptosis in primary CLL/SLL and follicular lymphoma cells, while BSO had minimal additive effects in these fresh cells. This appeared due to markedly lower intracellular GSH content within primary cells compared with cell lines (p 〈 0.001). Conclusion: Altogether, our findings establish that ATO has anti-lymphoma activity and approaches to enhance its cytotoxic activity are feasible via engagement of distinct cell death mechanisms. Continued investigation of arsenic-based therapy, including new arsenical compounds and methods of tissue delivery that are able to overcome mechanisms of cellular resistance, for the treatment of lymphoma is warranted. Disclosures: Gordon: Cure Tech: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2708.2708
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    Arsenic Trioxide (As2O3) Mediated Cell Death in Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL): Investigation of Reactive Oxygen Species (ROS), Caspase, and MAP Kinase Signaling Pathways.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2576-2576
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2576-2576
    Abstract: The cytotoxic activity of As2O3 in leukemia and myeloma has been shown to be mediated in part by ROS. We determined the mechanism of cytotoxicity of As2O3 in HL and NHL cell lines. Ramos, HF-1, SUDHL4 (NHL lines), and L428 (HL line) cells were cultured with increasing clinically relevant As2O3 concentrations (1.0mm-10mm) at 24-72 hours with and without the oxidizing agent, buthionine sulfoxime (BSO, 100mm), and with and without caspase inhibitors Z-VAD-FMK and Z-IETD-FMK. Apoptosis was measured by Annexin-V/propidium iodide (PI) staining and detected by flow cytometry (FACS). ROS was measured by oxidation of 2′7′ dichlorofluorescein diacetate (H2DCFDA) to Dichlorofluorescein (DCF) and analyzed by FACS. Immunoblots were performed for bcl-2, PARP, cleaved caspases 3, 8, 9, and mitogen activated protein kinase (MAPK) pathways (ERK, JNK, and p38 activation). As2O3 alone at 10mM resulted in dose- and time-dependent apoptosis in all cell lines (HL and NHL) with & gt;75% annexin+/PI+ between 48 and 72 hours. In Ramos and L428 cells, a combination of As2O3 (2 mM) and BSO 100mM resulted in & gt;80% annexinV+/PI+, while either agent alone resulted in & lt;15% apoptosis (p=0.001). A four-fold increase in ROS was seen in all four cell lines with As2O3/BSO, but not with As2O3 alone. Both ROS production and apoptosis induced by As2O3/BSO and As2O3 alone were reversible with the anti-oxidant N-acetylcysteine (NAC) (10mM). Furthermore, As2O3/BSO induced PARP cleavage and caspase-3 activation in all NHL cell lines, but not in L428. In Ramos, Z-VAD-FMK and Z-IETD-FMK blocked As2O3-induced apoptosis (suggesting a caspase-dependent mechanism), but had no effect on As2O3/BSO-induced cell death (caspase-independent). To investigate the signaling pathways involved, we performed western blot analysis for phospho-p38 (p-p38), phospho-JNK and phospho-ERK (p-ERK) in Ramos and L428 cells following As2O3 alone and As2O3/BSO. We found up-regulation of p-p38 in Ramos cells, while in L428, p-ERK was activated following As2O3 and As2O3/BSO. Inhibitors of p-38 in Ramos cells resulted in up-regulation of ERK. In summary, As2O3 induced dose- and time-dependent apoptosis in HL and NHL cell lines was significantly enhanced with the addition of BSO, and inhibited by NAC, suggesting that apoptosis was in part ROS-dependent. In Ramos, As2O3 alone resulted in caspase-dependent apoptosis, while addition of BSO resulted in caspase-independent apoptosis. As2O3 alone and combined with BSO resulted in activation of MAPK pathways in HL and NHL lines. These data provide a basis and a mechanism for As2O3-induced cell death in HL and NHL and have therapeutic implications.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.2576.2576
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    Triggered Release of Nanoparticulate Arsenic Trioxide for Treatment of Malignant Lymphomas: Preclinical Studies
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 4989-4989
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4989-4989
    Abstract: Lipid encapsulation of chemotherapeutic agents facilitates local delivery of highly concentrated antineoplastics to tumors while ensuring an adequate duration of drug exposure and reducing systemic toxicity. Using novel technology, we have encapsulated nanoparticulate (100 nM) arsenic trioxide (ATO) at high density in “nanobins,” biocompatible lipids and polymers that undergo a change in permeability when exposed to intracellular conditions, releasing drug cargo into the acidic tumor microenvironment (J. Am. Chem. Soc.2006, 128: 13348-9). At low concentrations, ATO is an effective agent in the treatment of acute promyelocytic leukemia, causing differentiation and turnover of PML. At higher but potentially toxic concentrations, ATO induces programmed cell death through the generation of reactive oxygen species and its effects on other proapoptotic signaling pathways. A preliminary dose-range finding study was completed comparing the toxicity profiles of free ATO and nanobin formulations of arsenic based on loading procedures using either cobalt (Co) or nickel (Ni). Female Balb/c mice were injected intraperitoneally with either a single dose of free or nanobin formulations of ATO at 20, 40, 60, 100 or 200 μmol/kg of elemental As. Mice were assessed daily for the first 5 days after injection and then every second day thereafter for a total study duration of 14 days and monitored for body weight and clinical signs. The maximum tolerated doses for both the Co- and Ni-ATO formulations were approximately 100 – 200 μmol/kg as a single intraperitoneal injection. Efficacy experiments for the Ni-ATO-nanobins were conducted in a murine (RAG2-M) xenograft model in which the mantle cell lymphoma cell line Z138C was injected subcutaneously. On day 21, when the average tumor volume was 50–100 mg, weekly injections of saline, empty nanobins, or the Ni-ATO nanobins at 60 μmol/kg were begun. Cohorts of mice received either two or three weekly injections. Mice bearing tumors of 1000 mm3 or greater were sacrificed. Results were normalized to the tumor size at the time that treatment was initiated (day 21) and are represented as fold-increase in tumor measured with calipers three times weekly. The results of the three weekly injections are illustrated below. Following two injections, the curves began to separate showing a significant inhibition of tumor growth that persists for two weeks beyond the last injection (p & lt; 0.001). Two weekly injections also impacted tumor growth significantly (p & lt; 0.01; data not shown). These results provide rationale for further preclinical investigation of this novel therapeutic. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.4989.4989
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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