Antiestrogens modulate the perforin/granzyme pathway of natural killer cell-mediated cytolysis

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Haeryfar, Seyed Mohammad Mansour
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Antiestrogenic drugs tamoxifen (TX) and toremifene (TO) are known to augment immune cytolysis in tumor targets induced by various killer cells. Here, we show that antiestrogens are capable of enhancing natural killer (NK) cell-mediated cytotoxicity against K562 erythroleukemia cell line and that both target and effector cells should be treated with antiestrogens in order for the maximal lysis to be achieved. K562 cells are Fas (CD95/Apo-1)-negative and treatment with antiestrogens had no influence on Fas expression. The presence of the Ca++ chelator EGTA/MgCl2 in the cytotoxicity assay totally abrogated K562 cytolysis and its antiestrogen-mediated augmentation, suggesting the involvement of the perforin/granzyme pathway. Treatment of K562 with the general caspase inhibitor zVAD-fmk did not inhibit specific cytotoxicity, indicating the caspase-independent nature of K562 immune cytolysis. When interleukin-2 (IL-2)-activated killer cells were subjected to antiestrogen pretreatment before being used against K562, cytotoxicity was significantly inhibited. In conclusion, antiestrogens, can affect the perforin/granzyme pathway of killer cell-mediated oncolysis.