المؤلفون: Yingming Jin, Wenbin Qian, Chunmei Yang, Haitao Meng, Hui Liu, Xue Yang, Liangshun You

المصدر: Journal of Hematology & Oncology

مصطلحات موضوعية: Male, Cancer Research, Apoptosis, mTORC1, mTORC2, chemistry.chemical_compound, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, Phosphorylation, Oxazoles, biology, Reverse Transcriptase Polymerase Chain Reaction, TOR Serine-Threonine Kinases, Myeloid leukemia, Perifosine, Drug Synergism, Hematology, Flow Cytometry, Leukemia, Myeloid, Acute, Oncology, Female, Signal Transduction, animal structures, Phosphorylcholine, Blotting, Western, SNS-032, Enzyme-Linked Immunosorbent Assay, Mechanistic Target of Rapamycin Complex 2, Mechanistic Target of Rapamycin Complex 1, Real-Time Polymerase Chain Reaction, Cyclin-dependent kinase, Humans, RNA, Messenger, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, Acute myeloid leukemia, Cell growth, Research, Akt, Cyclin-dependent kinases, Thiazoles, chemistry, Multiprotein Complexes, Cancer research, biology.protein, Proto-Oncogene Proteins c-akt

الوصف: Background Acute 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. Results SNS-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. Conclusion We 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d6d5a94ea3d4949bf6fa8f0d41b62eb1Test
http://europepmc.org/articles/PMC3599109Test

المؤلفون: Haitao Meng, Yingming Jin, Hui Liu, Liangshun You, Chunmei Yang, Xue Yang, Wenbin Qian

المصدر: Journal of Hematology & Oncology; 2013, Vol. 6 Issue 1, p1-14, 14p

مصطلحات موضوعية: CYCLIN-dependent kinase inhibitors, MTOR protein, ACUTE myeloid leukemia treatment, PROTEIN kinase B, CELLULAR signal transduction, CHOLINE, DRUG resistance, CELL death

مستخلص: Background: Acute 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. Results: SNS-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. Conclusion: We 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. [ABSTRACT FROM AUTHOR]

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