When this signaling complex was inhibited or down regulated, these lymphoma cel

Our results showed that a combination of sorafenib with VK1 induced apoptosis and caused typical apoptotic morphology changes, including condensed chromatin as well as nuclear fragmentation. The mechanisms by which combination sorafenib and VK1 synergistically induce apoptosis in glioma cells ap pear to be complex. The upregulation of buy abt263 the Raf MEK ERK cascade is one of the principal Ras regulated path ways, and has been proven to be associated with glioma cell proliferation, survival and migration, It has been suggested that downregulation of the Raf MEK ERK pathway may be of great promise as a target for prevent ing tumor cell growth, In the present study, west ern blotting analysis showed that low concentrations of sorafenib or VK1 when used as single agents did not inhibit phospho MEK and phospho ERK levels, whereas the combination of both agents had a strong synergistic action to inhibit phosphorylation of MEK and ERK.<br><br> These results suggest that the synergistic induction of cell apoptosis by combination of sorafenib and VK1 is, at least partly, attributed to inhibition of the Raf MEK ERK signaling pathway. One important target for chemotherapy is programmed cell death, and this is determined by the balance of proa poptotic and antiapoptotic purchase Adriamycin proteins. We also detected the Bcl 2 protein family, which regulates the mitochondrial pathway of apoptosis, The Bcl 2 family is composed of antiapoptotic and proapoptotic proteins.<br><br> buy ABT-199 The antiapoptotic Bcl 2 protein targets intracellular organelles such as the endoplasmic reticulum, outer mitochondrial and nuclear membranes, and then modulates tumor cells responses to apoptosis, Mcl 1 is another highly expressed antiapop totic protein in malignant tumors and has been implicated in resistance to chemotherapy through a number of signaling pathways, It has also been reported that ERK mediated phosphorylation is an important regulator of Mcl 1 stability, and downregulation of Mcl 1 is one of the main antitumor effect of sorafenib, either alone or in combination with other agents, on several kinds of tumor cells, In our study, the combination of low concen tration sorafenib and VK1 exhibited strong synergistic action by inhibiting protein expression of Bcl 2 and Mcl 1, leading to induction of cell apoptosis. However, there were no obvious changes in the expression of Bcl xl and Bax proteins.<br><br> These results suggested that the combination of sorafenib with VK1 induced apoptosis in BT325 and U251 cells through downregulating proa poptotic proteins Bcl 2 and Mcl 1. Conclusions The present study indicated that VK1 could enhance sorafenib induced growth inhibition and apoptosis of gli oma cells, and this synergistic effectiveness was associated with the downregulation of the Raf MEK ERK signaling pathway. These results make the combination of sorafenib and VK1 a promising therapeutic strategy against human malignant gliomas.