Deptor As a Target with Chemical Inhibitors; Alternative Therapy in Multiple Myeloma

Multiple myeloma (MM) is a hematological disorder characterized by a proliferation of malignant monoclonal plasma cells in the bone marrow (BM) and/or extramedullary sites. The increase in PFS and overall survival (OS) has been achieved through the introduction of high dose therapy (HDT) with autologous stem cell transplantation (SCT), and the introduction of thalidolamide, bortezomib and lenalidomide. Despite recent progress in OS rates, MM remains an incurable disease and most patients will relapse and require treatment. It is known that inhibition of deptor results in the inhibition of proliferation and induction of apoptosis in myeloma cells. In addition, high levels of deptor are predictive of a poor response to thalidomide in myeloma, indicating that levels of deptor expression is important as a prognostic marker for myeloma patients and would be a possible target for a novel therapeutic strategy, as using a small specific chemical inhibitor of deptor. In this study, we developed a novel small molecule chemical inhibitor (43 M) capable of inducing inhibition of the mTOR/Deptor interaction and results in negative regulation of the deptor that leads in the inhibition of proliferation and induces apoptosis in several cell lines of MM deptor-positive. This effect correlated with the Deptor expression level. The cytotoxic effect of 43 M depends on caspase activity. We analyzed potential mechanisms of 43 M, our findings showed that inhibition of Deptor/mTOR Pathway induces the activation of p70 and AKT. This leads to the induction of apoptosis. We analyzed whether the degradation of 43M-induced deptor-dependent proteosome complex using MG132, and this one prevent deptor degradation. Recent studies describe that the constitutive or inducible activation of the p38 MAPK pathway is considered an important molecular event contributing to the malignant phenotype of the tumor cell in MM. Therefore, these studies identify the interaction of p38 MAPK with Deptor as a new therapeutic target to improve the outcome of patients in MM. We analyzed the possible interaction of p38 MAPK with Debtor mediate a library in yeast. For confirmation of the possible interaction we analyzed the expression of p38 MAPK after treatment with 43 M, the data show that they induce an activation of p38 MAPK and that correlates inversely with the degradation of the deptor. However, simultaneous treatment of MM with 43M and SB203580 does not prevent the induction of 43M-mediated apoptosis. Additionally, the 43M effect was analyzed in a xenografic model of MM cell lines. 8226 MM cell lines were inoculated in 6-week Balb/C nu/ nu mice via s.c. When the tumor reached 500 mm3, they were inoculated on twice with 43 M at different concentrations per group (0, 20 or 40 mg / kg) and the tumor growth and the general state of the mice were subsequently analyzed. Tumor tissue was obtained and the expression of Deptor and 4E-BP1 by IHC was evaluated. The data showed that 43 M significantly inhibited tumor growth at the two doses tested 10 or 20 mg / kg and in tumors decreased the expression of Deptor and induction of 4E-BP1 activation. This study describes for the first time the possible role of Daptor as a therapeutic target using a chemical inhibitor capable of inducing a cytotoxic effect in cell lines positive for Deptor by inducing the degradation of this and activation p38 MAKP in the MM cell lines. In addition, Deptor is reported as an important therapeutic target in an in vivo MM model.