SNS-032 inhibits mTORC1-mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against AktReportar como inadecuado




SNS-032 inhibits mTORC1-mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Hematology and Oncology

, 6:18

First Online: 18 February 2013Received: 18 November 2012Accepted: 08 February 2013DOI: 10.1186-1756-8722-6-18

Cite this article as: Meng, H., Jin, Y., Liu, H. et al. J Hematol Oncol 2013 6: 18. doi:10.1186-1756-8722-6-18

Abstract

BackgroundAcute myeloid leukemia AML is a heterogeneous disorder with aberrant regulation of a variety of signal pathways. Therefore, simultaneous targeting of two or even more deregulated signal transduction pathways is needed to overcome drug resistance. Previously, it was reported that SNS-032, a selective cyclin-dependent kinase inhibitor, is an effective agent for treatment of AML; however, the molecular mechanisms of SNS-032-induced cell death of AML cells are not yet fully understood. The aim of the study was to characterize the effects in vitro of SNS-032, used alone and in combination with an Akt inhibitor perifosine, against AML cells and to identify the mechanism involved.

ResultsSNS-032 significantly induced cytotoxicity in human AML cell lines and blasts from patients with newly diagnosed or relapsed AML. However, Kasumi-1 cells and some of leukemic samples 14.9% from AML patients were resistant to SNS-032-mediated cell death. Western blot analysis showed that SNS-032 strongly inhibited the phosphorylation of mammalian target of rapamycin mTOR on Ser 2448 and Ser2481, and that removal of SNS-032 resulted in partial recovery of cell death and reactivation of phosphorylation of mTOR. Moreover, exogenous insulin-like growth factor-1 IGF-1 did not reverse SNS-032-induced cell growth inhibition and downregualtion of phosphor-mTOR at Ser2448 and Ser2481 although slight suppression of IGF-1R expression was triggered by the agent. Furthermore, SNS-032 at a lower concentration 60–80 nM enhanced AML cell cytotoxicity induced by perifosine, an Akt inhibitor. Importantly, SNS-032 treatment reduced colony formation ability of AML cells, which was significantly increased when two agents were combined. This combination therapy led to almost complete inhibition of Akt activity.

ConclusionWe conclude that SNS-032 might directly target mammalian target of rapamycin complex 1 mTORC1-mTORC2. Our results further provide a rationale for combining SNS-032 with perifosine for the treatment of AML.

KeywordsSNS-032 mTORC1 mTORC2 Cyclin-dependent kinases Perifosine Akt Acute myeloid leukemia Electronic supplementary materialThe online version of this article doi:10.1186-1756-8722-6-18 contains supplementary material, which is available to authorized users.

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Autor: Haitao Meng - Yingming Jin - Hui Liu - Liangshun You - Chunmei Yang - Xue Yang - Wenbin Qian

Fuente: https://link.springer.com/



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