| Autor: |
Vega GG; Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico., Franco-Cea LA; Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico., Huerta-Yepez S; Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México 'Federico Gómez', Mexico City 06720, Mexico., Mayani H; Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico., Morrison SL; 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., Bonavida B; 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., Vega MI; Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico. |
| Abstrakt: |
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. |
