Cross-Talk Cell Signaling between Anti-CD20 Antibodies and Nitric Oxide Donors

Rituximab (a chimeric anti-CD20 monoclonal antibody [mAb]) was the first U.S. Food and Drug Administration- approved therapeutic antibody for non-Hodgkin's lymphomas (NHLs). Although initially monotherapy treatments with anti-CD20 mAb were partially effective clinically, its combination with a cocktail of chemotherapeutic drugs (R-CHOP) resulted in significant improvement of clinical responses and progression free survivals. Several mechanisms have been reported on the underlying mechanisms of the activities of anti-CD20 mAbs; those consisted of ADCC, CDC, PCD, and inhibition of intracellular survival signaling pathways (leading to sensitization to both chemo and immunotherapeutic drugs). Such mechanisms share in common the pleiotropic effects of nitric oxide (NO) donors' treatment of B-NHL cells, including the inhibition of intracellular survival/anti-apoptotic pathways and the reversal of resistance of chemo-immunotherapeutic drugs. This review describes briefly both the mechanisms of activity of anti-CD20 antibodies and NO donors and establishes the presence of cell signaling cross-talks. Therefore, the combination of anti-CD20 and NO donors should result in the inhibition of tumor cell proliferation and the reversal of resistance of B-NHL cells. It is postulated that the combination use of well-designed subtoxic NO donors in combination with anti-CD20 mAbs should result in the improved treatment of patients who are initially unresponsive and/or are refractory to prior treatments.