The NF-κB inhibitors (bortezomib and DHMEQ) sensitise rituximab-resistant AIDS-B-non-Hodgkin lymphoma to apoptosis by various chemotherapeutic drugs

Rituximab in combination with chemotherapy is considered for the treatment of patients with AIDS-associated B-cell non-Hodgkin lymphoma (NHL); however, a subgroup of patients does not respond or develops resistance following initial treatments. To address the mechanism of rituximab-resistance, we have generated rituximab-resistant (RR) clones from wild-type (wT) 2F7. A representative 2F7-RR1 clone was examined for its response to rituximab treatment as well as rituximab-mediated chemosensitisation. In comparison with wT-2F7, 2F7-RR1 had less CD20 cell surface expression and failed to respond to rituximab-induced complement-dependent cytotoxicity (CDC) and apoptosis following cross-linking. In addition, rituximab failed to inhibit the constitutively activated p38 MAPK/NF-κB pathways and failed to sensitise 2F7-RR1 to various chemotherapeutic drugs (examples: taxol, vincristine, VP16, CDDP). In contrast to rituximab, treatment of 2F7-RR1 with the proteasome inhibitor, bortezomib, and the NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), resulted in inhibition of Bcl-2 expression and sensitisation of 2F7-RR1 to apoptosis by chemotherapeutic drugs. These findings demonstrate that rituximab resistance may be due to failure of rituximab to modify survival pathways. However, pharmacologic inhibitors that inhibit survival pathways can reverse RR tumor cells and sensitise the cells to apoptosis by various chemotherapeutic drugs. These findings offer novel potential therapeutic applications in the reversal of rituximab/drug resistant AIDS-derived B-NHL.