期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 47, 期 5, 页码 1735-1748出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2015.3170
关键词
lymphoma; rituximab-resistance; IFN-alpha; anti-CD20-hIFN-alpha; chemosensitivity; cytotoxicity
类别
资金
- CONACYT [275373]
- Jonsson Comprehensive Cancer Center
- UCLA AIDS Institute
- Fogarty International Center [D43 TW00013-14]
- Johnson Comprehensive Cancer Center at UCLA
- [FIS/IMSS/PROT/G13/1191]
- [IMSS R-2013-785-029]
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-hIFN alpha 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-hIFN alpha, but not with rituximab, IFN alpha, or rituximab+IFN alpha resulted in significant inhibition of cell proliferation and induction of cell death. Treatment with anti-CD20-hIFN alpha sensitized the cells to apoptosis by CDDP, doxorubicin and Treanda. Treatment with anti-CD20-hIFN alpha inhibited the NF-kappa B and p38 MAPK activities and induced the activation of PKC-delta and Stat-1. These effects were corroborated by the use of the inhibitors SB203580 (p38 MAPK) and Rottlerin (PKC-delta). Treatment with SB203580 enhanced the sensitization of the resistant clone by anti-CD20-hIFN alpha to CDDP apoptosis. In contrast, treatment with Rotterin inhibited significantly the sensitization induced by anti-CD20-hIFN alpha. Overall, the findings demonstrate that treatment with anti-CD20-hIFN alpha reverses resistance of B-NHL. These findings suggest the potential application of anti-CD20-hIFN alpha in combination with drugs in patients unresponsive to rituximab-containing regimens.
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