Treatment of Tumor Cells with Non-steroidal Anti-inflammatory Drug Sulindac Increases Survival and Function of Immune Effectors

Objectives: NSAIDs have anti-proliferative effect against a variety of cancer cells and are used as a chemopreventive drugs for colon cancer as well as orally derived cancers. The objective of our studies is to investigate the effect of sulindac treatment of tumor cells in increased survival and function of immune cells. NSAIDs exert their beneficial effect partly by inhibiting NFkB. Methods:We have previously shown that the inhibition of NFkB in HEp2 cells prior to their co-incubation with the NK or CD8+ T cells is responsible for increased immune survival and function. Thus, we treated HEp2 cells with different concentrations of Sulindac and subsequently co-cultured them in the presence of Peripheral Blood Lymphocytes (PBL) and Natural Killer cells derived from healthy donors. Results:PBLs and the NK cells were capable of lysing sulindac treated HEp2 cells significantly. Furthermore, co-cultured of PBLs or NK cells with the sulindac treated HEp2 cells augmented cytokine secretion by immune cells, and the levels of released cytokines by the immune cells approached the levels of which were observed when the immune cells were co-cultured in the presence of NFkB knock out HEp2 cells using a IkB super-repressor. The increased immune activation by sulindac treated HEp2 cells was specific since the treatment with Adriamycin , a drug which also demonstrates significant anti-tumor activity, did not changed the levels of cytokine secretion by the immune cells. Conclusions:In conclusion our data indicates that sulindac not only is capable of inhibiting tumor growth, but also it is important in promoting survival and function of immune cells. Tumor cells are capable of inactivating the immune cells by a variety of mechanisms. Therefore, by preventing such inactivation by sulindac, immune cells will be capable of mounting their anti-tumor activity as well as establishing a long-term immunological memory.RO1DE12880