Synergistic Killing Effect Of NF - κB Inhibitor And JNK Inhibitor On Leukemia Cells

NF-κkB becomes an anti-leukemia drug because it can specifically inhibit growth of leukemia stem cells. Because of its potential side-effects, its clinical application is limited. The toxic effects are mainly due to inflammatory induced normal cell death. We found that, except survival signaling mediated by NF-κB, TNF-a also induces programmed necrosis mediated by RIP1/RIP3in normal HSPCs and proliferation/survival signals such as JNK which is independent on NF-κB in leukemia cells(LC). Inhibition of JNK signaling can not only protect the HSCP against the destruction by NF-κB inhibitors, but also promote the killing effect of NF-κB inhibitors on the LC. The main purpose of our subject is to study the possibility of combination JNK inhibitors with NF-κkB inhibitors to treat leukemia.NF-κB and JNK signal pathways involve in regulating many important cellular process such as cell proliferation, differentiation, apoptosis. Deregulation of NF-κB and JNK signaling is commonly detected in leukemia, suggesting the important role of these two signaling pathways in the pathogenesis of leukemia. In this study, using Jurkat cells and K562cells, we evaluated the effects of NF-κB inhibitor and JNK inhibitor alone or in combination on the proliferation, survival and clonegenic capacity of leukemic cells. Cell proliferation and apoptosis were detected by CFU, MTT, Western Blot, Wright-Giemsa staining and Annexin V-staining assays. We found that NF-κB and JNK induce two parallel survival signals in leukemic cells. Inactivation of NF-κB leads to activation of JNK signaling. Inhibition of either NF-κB or JNK was able to induce apoptosis in leukemic cells. The killing effect of NF-kB or JNK inhibitor on leukemic cells is significantly correlated to the concentration of inhibitors. The combination of two inhibitors had synergistic killing effects on leukemic cells. Interestingly, JNK induces a death signal in normal hematopoietic stem/progenitor cells (HSPC)(P<0.01). JNK inhibitor treatment partially protects HSPC from NF-κB inhibitor induced cell death. Our data suggested that the combination of NF-κB inhibitor and JNK inhibitor might provide a better treatment on leukemia by synergistic killing leukemic cells simultaneously prevents normal HSPC.