[Frontiers in Bioscience 16, 770-782, January 1, 2011]

Understanding rituximab function and resistance: implications for tailored therapy

Alfredo Amoroso1, Sameh Hafsi1,2, Loredana Militello1, Alessia E. Russo1, Zohra Soua2, Maria C. Mazzarino1, Franca Stivala1, Massimo Libra1

1Department of Biomedical Sciences, University of Catania, Catania, Italy, 2Faculty of Medicine, Laboratory of Biochemistry, Sousse, Tunisia

TABLE OF CONTENTS

1. Abstract
2. Non Hodgkin's Lymphomas
3. Rituximab and CD20: structure and function g
3.1. Rituximab mechanisms of action
3.1.1. ADCC
3.1.2. CDC
3.1.3. Induction of apoptosis
3.1.3.1. Activation of Src family tyrosine kinases
3.1.3.2. Activation of Fas apoptotic pathway
3.1.4. Inhibition of survival and antiapoptotic signaling pathways
3.1.4.1. Inhibition of the p38 MAPK/STAT3/NF-kB/SP1/Bcl-2 pathway
3.1.4.2. Inhibition of the Src/Raf 1/MEK1/2/ERK1/2/AP-1/Bcl-xL pathway
3.1.4.3. Inhibition of the NF-kB/Bcl-xL pathway
3.1.4.4. Inhibition of the PI3K/AKT/Bcl-xL pathway
4. Mechanisms of resistance to Rituximab
4.1. Preceding CD20 binding
4.2. After CD20 binding
5. Conclusion
6. References

1. ABSTRACT

The addition of anti-CD20 monoclonal antibody (rituximab) to chemotherapy has significantly improved survival in B-cell lymphoma. However, a substantial number of patients relapse after treatment with rituximab. Understanding of anti-CD20 antibody molecular function may facilitate the development of pharmacologic strategies to overcome resistance. Cell death have been demonstrated to be caused by rituximab binding to CD20 throughout direct and indirect mechanisms. The direct mechanism comprises growth inhibition, induction of apoptosis and sensitization of cells to chemotherapy. While, the indirect mechanisms to Rituximab include complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). However, these mechanisms are still poorly understood. To shed light on this issue, we have analyzed the most significant results showing the role of Rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Mechanisms of resistance to Rituximab are also discussed. Additionally, studies here reported show that, cellular targets are modified after treatment with Rituximab and may become useful for novel therapeutic strategies in the treatment of patients resistant to standard therapy.