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Betulinic acid trig...
Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors
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- Fulda, S. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Friesen, C. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Los, Marek Jan (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Scaffidi, C. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Mier, W. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Benedict, M. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Nunez, G. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Krammer, P. H. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Peter, M. E. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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- Debatin, K. M. (author)
- Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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(creator_code:org_t)
- American Association for Cancer Research, 1997
- 1997
- English.
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In: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 57:21, s. 4956-4964
- Related links:
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http://cancerres.aac...
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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Abstract
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- Betulinic acid CBA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1 beta-converting enzyme/Ced-3-like proteases), FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-x(L) conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, pax and Bcl-x(s), two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- cancer-therapy
- chemotherapy-induced apoptosis
- crma-inhibitable protease
- expression
- factor receptor superfamily
- fas ligand
- induced cell-death
- molecular-cloning
- signaling complex
- t-cells
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Fulda, S.
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Friesen, C.
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Los, Marek Jan
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Scaffidi, C.
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Mier, W.
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Benedict, M.
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Nunez, G.
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Krammer, P. H.
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Peter, M. E.
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Debatin, K. M.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Cancer Research
- By the university
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Linköping University