Induction of Apoptosis Antiproliferation

Apoptosis is a process of programmed cell death by which cells undergo organized self-destruction. Classical apoptosis is caused by the activation of caspases, a family of intracellular cysteine proteases, although apoptosis may occur without activation of caspases in some situations (3). There are at least two major pathways of caspase activation in caspase-dependent apoptosis. The intrinsic, or mitochondrial-mediated pathway induces apoptosis through the bcl-2 family of proteins and activation of caspase 9. The extrinsic, or death receptor-mediated pathway induces activation of caspase 8. These two caspases (caspase 8 and 9) subsequently activate caspase 3. The intrinsic pathway is dependent on activated Bak/Bax and is inhibited by bcl-2 proteins (Fig. 1) (11,12). Although there have been some controversial results in recent investigations, bcl-2 proteins appear to block the intrinsic apoptosis pathway by inhibiting caspase activity (3).

In an in vitro model, exposure of lymphoma cells to rituximab resulted in the activation of the Src-family of protein tyrosine kinases (13), leading to the phosphorylation of PLC^2, which induces calcium influx and activates caspase 3, resulting in promotion of apoptotic cell death (8,14). Another in vitro model showed that exposure to rituximab resulted in the sustained phosphorylation of p38-MAPK, JNK, and ERK kinases

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).

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).

in lymphoma cells (15). Also, rituximab-induced translocation of CD20 into lipid rafts is known to be crucial calcium influx, resulting in apoptosis (8,13,16).

Recent studies showed that rituximab down-regulates interleukin-10 (IL-10) in some lymphoma cell lines (17,18,19,20,21,22,23,24,25,26,27). IL-10has a stimulatory function as an autocrine or paracrine growth factor for lymphoma cells (28). IL-10 is a known promoter of BCL2 expression in hematopoietic cells (29) as well as lymphoma cells (28). Rituximab is known to induce down-regulation of IL-10 expression and consequently of bcl-2 protein expression, making B-cells more susceptible to apoptotic signals (Fig. 1) (30,31,32). However, the implication of IL-10 on clinical outcome after rituximab therapy is still unclear.

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