It was previously reported that highly CK2a positive leukemia cells are selleck inhibitor more sensitive to apigenin induced cell death than are CK2a leukemia cells with relatively low levels of CK2a. However, in this study, we observed that the sensitivity of MM cells to apigenin induced cell death depended on whether apigenin effectively inhibited CK2 kinase activ ity, decreased Inhibitors,Modulators,Libraries CK2a protein levels, decreased the phos phorylation of Cdc37 and induced the degradation of Hsp90/Cdc37 client kinases. Consistent with these observations, one of the primary MM cell samples in our analysis exhibited high CK2a expression but had low sensitivity to apigenin, whereas the CK2a low U266 cells were more sensitive to apigenin than CK2a high RPMI 8226 cells.

We are currently investigating possible explanations for the failure of apigenin to sup press CK2 activity in particular MM cells. Importantly, apigenin did not inhibit CK2 activity or exhibit any cytotoxic effects in PBMCs. Api genin mediated suppression of CK2 activity was accom panied by reduced phosphorylation of Cdc37 in MM cells, leading to the disassociation of Hsp90/Cdc37/cli ent Inhibitors,Modulators,Libraries protein complexes and inducing the degradation of client kinase proteins Inhibitors,Modulators,Libraries including RIP1, Raf 1, Src, Cdk4, and AKT via the ubiquitin proteasome pathway. Since some kinases, such as RIP1, Raf 1 and Src, locate at the upstream of various signal pathways, the degradation of these kinase proteins could lead to the abrogation of their downstream pathways. These findings help to explain how apigenin can inhibit many signaling pathways.

In addition to apigenin, resveratrol Inhibitors,Modulators,Libraries and epigallocatechin 3 gallate have been reported to induce apoptosis by significantly downregu lating CK2 activity in both ALVA 41 and PC 3 prostate cancer cells. Bioactive polyphenolic Inhibitors,Modulators,Libraries and flavonoid compounds have demonstrated potential in cancer ther apy and cancer chemoprevention, and further studies are needed to determine if CK2 is the common target of these compounds. The possibility that Cdc37 is a sec ondary target also requires further assessment. Among the kinases affected by apigenin treatment, receptor interacting protein 1 is of special inter est. It has not been determined if RIP1 is a Cdc37 client kinase, but it has been shown that the stability of RIP1 is dependent on Hsp90 chaperone function. Recent studies have demonstrated that selleck products RIP1 kinase is a key pro tein in the cellular decision of cells to live or die upon exposure to different stress signals. Depending on the cellular context and stimulation, RIP1 kinase may participate in three different signal complexes, which have various functions with respect to mediating the activation of NF B, apoptosis, or necroptosis.