Overcoming rituximab drug-resistance by the genetically engineered anti-CD20-hIFN-α fusion protein: Direct cytotoxicity and synergy with chemotherapy

Vega,Gabriel  G.; Franco-Cea,Luz  Areli; Huerta-Yepez,Sara; Mayani,Héctor; Morrison,Sherie  L.; Bonavida,Benjamin; Vega,Mario  I.

doi:10.3892/ijo.2015.3170

Overcoming rituximab drug-resistance by the genetically engineered anti-CD20-hIFN-α fusion protein: Direct cytotoxicity and synergy with chemotherapy

Authors:
- Gabriel G. Vega
- Luz Areli Franco-Cea
- Sara Huerta-Yepez
- Héctor Mayani
- Sherie L. Morrison
- Benjamin Bonavida
- Mario I. Vega
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Affiliations: Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico, Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México ‘Federico Gómez’, Mexico City 06720, Mexico, 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
Published online on: September 16, 2015 https://doi.org/10.3892/ijo.2015.3170
Pages: 1735-1748

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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.

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