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Rituximab has been used in the treatment of B Non-Hodgkin’s Lymphoma (NHL) with significant clinical responses. However, a subset of patients fails to respond to treatment with rituximab used alone or in combination with chemotherapy. The mechanism by which B-NHL patients resist treatment is not known. We have reported that treatment of the AIDS B-NHL cell line 2F7 with rituximab resulted in significant inhibition of the p38 MAPK pathway and inhibition of Bcl-2 expression concomitantly with chemoresistance. The pivotal role of Bcl-2 in chemoresistance was demonstrated by various methods as inhibition of Bcl-2 expression or activity sensitized the tumor cells to drug-induced apoptosis (Oncogene, 23(20):3530-40, 2005). In order to examine the mechanism of NHL resistance to rituximab, we have developed in the laboratory rituximab-resistant clones of 2F7 (2F7RR) and have compared their response with the wild type to rituximab treatment alone and with the combination of chemotherapeutic drugs. Unlike the wild type 2F7, rituximab treatment failed to sensitize 2F7 RR1 to drug-induced apoptosis, failed to modulate the p38MAPK/NF-κB/YY1/STAT3 signaling pathways, did not inhibit Bcl-2 expression, and failed to chemosensitize the tumor cells. We examined the effect of various chemical inhibitors of this signaling pathway on chemosensitization. We demonstrate that treatment with the proteasome inhibitor Bortezomib or the NF-kB inhibitor DHMEQ significantly sensitized 2F7-RR1 cells to drug (CDDP, vincristine, adriamycin, VP16, taxol)-induced apoptosis. These inhibitors also resulted in the inhibition of NF-kB, YY1 and downregulated Bcl-2 expression. These findings demonstrate that rituximab and drug-resistant clone 2F7-RR1 can be sensitized to reverse chemoresistance. The findings also identify intracellular targets whose modification can reverse resistance. Such targets include the p38 MAPK pathway, the transcription factors NF-kB, YY1, or STAT3 and also inhibitors of Bcl-2 expression and/or activity. These findings also suggest that combination treatment of currently used drugs such as Bortezomib and chemotherapeutic drugs have a potential for the treatment of rituximab and drug-resistant AIDS-B-NHL. This study was supported in part by a philanthropic contribution from the JCCC/Rosenfield Fund under the direction of David Leveton.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]