Service and stabilization of the p53 by JNK signaling is explained in p53 null mouse fibroblast.1S cells prevented the killing of cells mediated by RITA. These results further make sure RITA induced apoptosis inMM natural product libraries cells is p53 dependent. Having found that RITA induces apoptosis via activation of the JNK signaling pathway, we further examined the combined cytotoxic effect of RITA and DXM, a chemotherapeutic along with an activator of JNK. The consequences of combination of RITA and DXM were evaluated to the stability of MM cell lines and primary MM examples. We examined probable additive or synergistic anti proliferative effects of DXM and RITA following 48 hours of treatment of H929 cells with lower doses of RITA combined with 0. 5 mM DXM. Treatment of H929 cells with RITA or DXM alone induced only 10 to 400-word cell killing which was synergistically enhanced to 65% and 80%, respectively in RITA plus DXM combination. We next proved the cytotoxic reaction of RITA in conjunction with DXM in MM patient samples. The combination pyrazine of 1 mM DXM and 5 mM RITA caused a complete cytotoxicity in 3 primary MM samples. The synergistic antimyeloma action of the two agencies was obviously demonstrated by way of a leftward shift of the dose response curve together with isobologram and CI analyses in both H929 cell lines and main MM products. To further understand the clinical importance of JNK activation in RITA induced apoptosis we examined the cytotoxic effect of RITA by mixing it with CDDO, a known JNK activator. First, dose responses of CDDO were analyzed in MM. 1S and H929 cells after treating the cells with different concentrations of CDDO for 48 hrs. Results showed a dose-dependent killing of MM cells by CDDO. Next, MM. 1S or H929 cells were treated with low doses of RITA with a fixed amount of CDDO for 48 hrs and stability was tested. As shown in Figure S3B, in MM. 1S cells the mix of 0. 5 mM CDDO with either 0. 25 or 0. 5 mM RITA displayed a complete cytotoxic reaction with a CI value of 0. 83 and 0. 62, respectively. e3 ubiquitin ligase complex Similarly, mix of 0. 5 mM CDDO with 0. 5 or 1. 0 mM RITA showed a synergistic cytotoxic reaction in H929 cells by which CI value was 0. 92 and 0. 87, respectively. In this study, we demonstrated that RITA induces a powerful activation of JNK signaling in MM cells. GEP by microarray discovered a substantial number of genes related to stress reactions resulting in apoptosis. In keeping with the of c Jun as witnessed by microarray studies, we discovered that RITAinduces phosphorylation of c Jun in MM cells in a period and dosedependent manner which causes activation of p53 and cell death. These results suggest the activation of JNK signaling in MM cells upon stimulation by RITA. Activation of JNK by hgal9, or plinabulin, or perifosine has previously been reported in MM cells. Accumulating evidence has demonstrated that during apoptotic signaling, activity of both of p53 and c Jun, may be modulated through posttranslational modifications by JNK cascade.