Since these molecules are related with drug resistance, down regulation of P gp, DNA PKcs, pAkt, and pGSK 3b after treatment with TRAIL might lead to the hyper sensitivity to MDR related drugs of MDR variant of CEM cells. Indeed, inhibition http://www.selleckchem.com/products/Perifosine.html of Akt enhances suscept ibility to TRAIL by up regulation of death receptors and down regulation of c FLIP and down regulates Inhibitors,Modulators,Libraries P gp expression in multidrug resistant human T acute leukemia. Our study also showed that anti apoptotic Bcl 2 and Mcl 1 proteins were over expressed in CEM/VBL100 cells and the levels of these proteins and Bax were sig nificantly decreased and increased by Bcl 2 and Mcl 1, the antiapoptotic Bcl 2 family proteins, were over Inhibitors,Modulators,Libraries expressed in CEM/VBL100 cells in comparison with CEM cells, and the levels of these anti apoptotic pro teins and Bax were significantly decreased and increased by treatment of TRAIL in CEM/VBL100 cells, respectively, suggesting that TRAIL induced apoptosis of MDR cells was mediated through mitochondria dependent pathway as well as caspase activation.

Bcl 2 and Mcl 1 are often highly expressed Inhibitors,Modulators,Libraries in chemother apy resistant cancers and Inhibitors,Modulators,Libraries prevents apoptosis by inacti vating pro apoptotic Bax and Bak. The increased expression of Bcl 2 or Bcl xL was the com mon feature of P gp related drug resistant human leu kemic ce1l lines. Over expression of Mcl 1 decreased sensitivity of leukemia cells to cytotoxic che motherapeutic agents and specific down regula tion of Mcl 1 via RNA interference sensitized multidrug resistant leukemia cells towards chemother apy and induced apoptosis.

Therefore, the reduc tion of Bcl 2 and Mcl 1 after exposure to TRAIL may be in part a cause of Inhibitors,Modulators,Libraries TRAIL induced sensitization of CEM/VLB100 cells to MDR related drugs. Moreover, our data showed the cleavage of selleck chemicals llc P gp and DNA PKcs by treatment with TRAIL. Recently, it has been shown that the cleavage of P gp is dependent on caspase 3 during apoptotic cell death induced by LY294002, H2O2, and Z LEHD FMK in MDR variant of CEM cells. DNA PKcs is also a substrate of caspase 3. Here, we demonstrated that the degradation of P gp and DNA PKcs during treat ment of CEM/VLB100 cells with TRAIL was a caspase 3 dependent manner. This result was followed by the sig nificant reduction of rhodamine123 efflux and the increased sensitivity to MDR related drugs such as VLB and DOX after exposure to TRAIL in CEM/VLB100 cells, suggesting that the degradation of P gp as well as the down regulation of Bcl 2 and Mcl 1 could be involved in sensitization of MDR cells to MDR related drug after treatment with TRAIL.