Since the gangliosides GD3 and GD1b are absent in the cell membrane most of EL 4 cells, the anti GD2 mAb ME361 could only interact with ganglioside GD2, and cross reactivity of these antibodies with Inhibitors,Modulators,Libraries other gangliosides did not contribute to observed cytotoxic effect of these anti bodies. Thus, our results point out the predominant role of GD2 in the reception of cytotoxic signals induced by two types of anti GD2 antibodies. To further prove the exclusive role of ganglioside GD2 in a reception of cytotoxic signal, we reduced the expres sion level of GD2 on the surface of EL 4 tumor cell line, and these cells with decreased expression of GD2 were used to study cytotoxic effects of anti GD2 mAbs.

Com parison of the efficiency of anti GD2 mAb induced cyto toxic effects in intact cells versus cells with Inhibitors,Modulators,Libraries reduced expression of GD2 allowed us to directly assess the con tribution of this ganglioside in induction of cell death. Inhibition of the enzymes responsible for the ganglioside synthesis let us to obtain the cells with significantly reduced expression of GD2. The cytotoxic effect caused by anti Inhibitors,Modulators,Libraries GD2 mAbs was much higher for intact cells than for cells with inhibited expression of GD2. Thus, we demonstrated that ganglioside GD2 itself could serve as a receptor of cell death in GD2 positive tumor cells. However, several important questions remain unclear 1 how does the GD2 transmit a cell death signal inside the cell. 2 what causes the variability in efficiency of the cytotoxic effect induced by the different anti GD2 mAbs.

3 whether the property of GD2 molecule being a recep tor of death signal is a general feature of other tumor associated gangliosides The published reports regarding the role of ganglio sides in regulation of cell death are rather conflicting and contradictory. Inhibitors,Modulators,Libraries The researchers have incoherent points of view about the mechanisms of the cytotoxic action of antibodies to the tumor associated ganglio sides. Thus, a number of researchers have observed cer tain aspects of apoptotic cell death in the cells exposed to the GD2 and NeuAcGD2 Inhibitors,Modulators,Libraries specific antibodies. On the other hand, it was shown that antibodies to tumor associated ganglioside NeuGcGM3 induced cell death by mechanism of necrosis with formation of the membrane pores. The researchers showed that this process is caspase independent.

Such results could be explained by both the different origin of tumor cell lines used in these studies, and by targeting different tumor associated gangliosides. currently Also it was reported that caspases did not play a key role and did not determine the mechanism of cell death triggered by anti GD2 mAbs. According to this study, cell death signaling pathways triggered by anti GD2 mAbs are com plex and could be attributed to non classical mechanisms of cell death, with features of apoptosis and necrosis, and with involvement of mitochondria dependent pathways.