Rituximab pathway

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

It has been proposed that rituximab also functions through the complement-dependent cytotoxicity (CDC) pathway, specifically the classical pathway, which requires... 

In summary, the mechanism of monoclonal antibody activity for CLL might be different from that for lymphoma. Besides ADCC, other pathways such as caspase-dependent apoptosis or CDC are more likely to contribute to rituximab or alemtuzumab-induced clearance of CLL cells in vivo. 

There is increasing evidence that complement plays a role in the clinical response to rituximab. However, little data is available regarding the polymorphism of genes involved in the complement-mediated pathway. 

Jazirehi AR, Vega MI, Chatterjee D et al. Inhibition of the Raf-MEKl/2-ERKl/2 signaling pathway, Bel-xL down-regulation, and ehemosensitization of non-Hodgkin s lymphoma B-cells by Rituximab. Cancer Res 2004 64 7117-7126. 

Jazirehi AR, Bonavida B. 2005. Cellular and molecular signal transduction pathways modulated by rituximab (Rituxan, anti-CD20 mab) in non-Hodgkin s lymphoma Implications in characterization of therapeutic intervention. Oncogene. 24 2121-2143. 

Jazirehi, A.R., Huerta-Yepez, S., Cheng, G., and Bonavida, B. (2005). Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor- kappa )B signaling pathway in non-Hodgkin s lymphoma B-cell lines role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Res. 65, 264-276. 

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