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Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity
Roque Navarro, Lourdes; Chakrabandhu, Krittalak; Rodr¨ªguez, Sandra; Toledo, Carlos; Carr, Adriana; Mateo de Acosta, Cristina; Odile Hueber, Anne; P¨¦rez, Rolando; Le¨®n, Joel de.
Affiliation
  • Roque Navarro, Lourdes; Antibody Engineering Department. Centre of Molecular Immunology. Havana. Cuba
  • Chakrabandhu, Krittalak; Institute of Signaling, Developmental Biology and Cancer Research. Havana. Cuba
  • Rodr¨ªguez, Sandra; Electronic Microscopy Department. National Centre of Scientific Investigations. Havana. Cuba
  • Toledo, Carlos; Criminality Central Laboratory. Havana. Cuba
  • Carr, Adriana; Antibody Engineering Department. Centre of Molecular Immunology. Havana. Cuba
  • Mateo de Acosta, Cristina; Antibody Engineering Department. Centre of Molecular Immunology. Havana. Cuba
  • Odile Hueber, Anne; Institute of Signaling, Developmental Biology and Cancer Research. Havana. Cuba
  • P¨¦rez, Rolando; Antibody Engineering Department. Centre of Molecular Immunology. Havana. Cuba
  • Le¨®n, Joel de; Antibody Engineering Department. Centre of Molecular Immunology. Havana. Cuba
Mol Cancer Ther ; 7(7): 2033-2041, July, 2008. ilus, graf
Article in En | CUMED | ID: cum-39789
Responsible library: CU1.1
ABSTRACT
Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid¨Ccontaining gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4+ T lymphocytes) that expressed the antigen. Impairment of ganglioside synthesis in tumor cells abrogated the 14F7 mAb cytotoxic effect; however, exogenous reincorporation of the ganglioside did not restore tumor cell sensitivity to 14F7 mAb-induced cytotoxicity. 14F7 F(ab¡ä)2 but not Fab fragments retained the cytotoxic capacity of the whole mAb. By contrary, other mAb, which recognizes N-glycolylated gangliosides, did not show any cytotoxic effect. These mAbs showed quite different capacities to bind NGcGM3-positive cell lines measured by binding inhibition experiments. Interestingly, this complement-independent cell death mechanism did not resemble apoptosis, because no DNA fragmentation, caspase activation, or Fas mediation were observed. However, NGcGM3 ganglioside-mediated 14F7 mAb-induced cell death was accompanied by cellular swelling, membrane lesion formation, and cytoskeleton activation, suggesting an oncosis-like phenomenon. This novel mechanism of cell death lets us to support further therapeutic approaches using NGcGM3 as a molecular target for antibody-based cancer immunotherapy(AU)
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Full text: 1 Collection: 06-national / CU Database: CUMED Main subject: Cell Membrane / Antibodies, Monoclonal / Neoplasms Limits: Animals Language: En Journal: Mol Cancer Ther Year: 2008 Document type: Article
Full text: 1 Collection: 06-national / CU Database: CUMED Main subject: Cell Membrane / Antibodies, Monoclonal / Neoplasms Limits: Animals Language: En Journal: Mol Cancer Ther Year: 2008 Document type: Article