Figure 2.

Schematic presentation of the cytotoxic pathways, induced in cancer cells by the complement C5b-9, the counteractive cellular resistance mechanisms, and postulated approaches to overcome this cancer evasion. Following the binding of antibodies to cancer cells, the complement system is activated and deposits C4b and C3b molecules that serve as initiators of C3/C5 convertase activation. The C5 convertases initiate the activation of the terminal complement pathway and the formation of the C5b-9 complexes (24). Upon insertion of the C5b-9 complexes into the plasma membrane of cancer cells, they induce calcium ion influx and activate pro- and anti-lytic signals. This scheme depicts the proteins proposed to be involved in the ensuing cancer cell death (encircled) and the proteins protecting the cancer cells from the lytic processes. Extracellular (gray boxes) and intracellular (purple boxes) protective proteins are indicated. Several reagents (white boxes) that will block the protective proteins are indicated and proposed for adjuvant therapy to therapeutic antibodies. Ab, antibody; Bcl-2, B-cell lymphoma/leukemia-2; BH3, Bcl-2 homolog domain-3; Bid, BH3 interacting domain death agonist; CK2, casein kinase 2; ERK, extracellular signal-regulated kinase; HSP90, heat shock protein 90; HSP70, heat shock protein 70; JNK, c-jun N-terminal kinase; MAC, complement membrane attack complex; MLKL, mixed lineage kinase domain-like protein; MMP, matrix metalloproteinase; PKC, protein kinase C; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor-interacting protein kinase 3; serine-, serine protease; siRNA, small interfering RNA.