Overcoming rituximab drug-resistance by the genetically engineered anti-CD20-hIFN-a fusion protein: Direct cytotoxicity and synergy with chemotherapy
Por:
Vega G.G., Franco-Cea L.A., Huerta-Yepez S., Mayani H., Morison S.L., Bonavida B., Vega M.I.
Publicada:
1 ene 2015
Resumen:
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 rituximabresistant 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-hIFNa 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-hIFNa, but not with rituximab, IFNa, or rituximab+IFNa resulted in significant inhibition of cell proliferation and induction of cell death. Treatment with anti-CD20-hIFNa sensitized the cells to apoptosis by CDDP, doxorubicin and Treanda. Treatment with anti-CD20-hIFNa inhibited the NF-?B and p38 MAPK activities and induced the activation of PKC-s and Stat-1. These effects were corroborated by the use of the inhibitors SB203580 (p38 MAPK) and Rottlerin (PKC-s). Treatment with SB203580 enhanced the sensitization of the resistant clone by anti-CD20-hIFNa to CDDP apoptosis. In contrast, treatment with Rotterin inhibited significantly the sensitization induced by anti-CD20-hIFNa. Overall, the findings demonstrate that treatment with anti-CD20-hIFNa reverses resistance of B-NHL. These findings suggest the potential application of anti-CD20-hIFNa in combination with drugs in patients unresponsive to rituximab.containing regimens.
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