title: Overcoming rituximab drug-resistance by the genetically engineered anti-CD20-hIFN-α fusion protein: Direct cytotoxicity and synergy with chemotherapy.
abstract: Treatment of patients with B-NHL with rituximab and CHOP has resulted in significant clinical responses. However, a subset of patients develops resistance to further treatments. The mechanism of unresponsiveness in vivo is not known. We have reported the development of rituximab-resistant clones derived from B-NHL cell lines as models to investigate the mechanism of resistance. The resistant clones exhibit hyper-activated survival/anti-apoptotic pathways and no longer respond to a combination of rituximab and drugs. Recent studies reported the therapeutic efficacy in mice bearing B-cell lymphoma xenografts following treatment with the anti-CD20-hIFNα fusion protein. We hypothesized that the fusion protein may bypass rituximab resistance and inhibit survival signaling pathways. Treatment of the rituximab-resistant clones with anti-CD20-hIFNα, but not with rituximab, IFNα, or rituximab+IFNα resulted in significant inhibition of cell proliferation and induction of cell death. Treatment with anti-CD20-hIFNα sensitized the cells to apoptosis by CDDP, doxorubicin and Treanda. Treatment with anti-CD20-hIFNα inhibited the NF-κB and p38 MAPK activities and induced the activation of PKC-δ and Stat-1. These effects were corroborated by the use of the inhibitors SB203580 (p38 MAPK) and Rottlerin (PKC-δ). Treatment with SB203580 enhanced the sensitization of the resistant clone by anti-CD20-hIFNα to CDDP apoptosis. In contrast, treatment with Rotterin inhibited significantly the sensitization induced by anti-CD20-hIFNα. Overall, the findings demonstrate that treatment with anti-CD20-hIFNα reverses resistance of B-NHL. These findings suggest the potential application of anti-CD20-hIFNα in combination with drugs in patients unresponsive to rituximab-containing regimens.
authors.affiliation: Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Vega
authors.affiliation: Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico.
authors.forename: Luz Areli
authors.initials: LA
authors.lastname: Franco-Cea
authors.affiliation: Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México 'Federico Gómez', Mexico City 06720, Mexico.
authors.forename: Sara
authors.initials: S
authors.lastname: Huerta-Yepez
authors.affiliation: Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico.
authors.forename: Héctor
authors.initials: H
authors.lastname: Mayani
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center and David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sherie L
authors.initials: SL
authors.lastname: Morrison
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center and David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
authors.affiliation: Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico.
authors.forename: Mario I
authors.initials: MI
authors.lastname: Vega
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000235:genetics* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D016898:Interferon-alpha / Q000235:genetics* / Q000627:therapeutic use; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage; D000069283:Rituximab / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018951:Antigens, CD20; D007093:Imidazoles; D016898:Interferon-alpha; D015514:Oncogene Proteins, Fusion; D011725:Pyridines; D000069283:Rituximab; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580