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However, whether melatonin has selective effects against FLT3-ITD-positive AML cells remain unclear and have attracted our research interest.
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Melatonin can also enhance anti-leukemia activity of retinoic acid in HL60 cells. Melatonin was also reported to induce caspase-dependent apoptosis in human leukemia Molt-3 cells, and inhibit MLL-rearranged leukemia through suppressing the RBFOX3/hTERT and NF-κB/COX-2 signaling pathways. Recent studies showed that melatonin synergizes the chemotherapeutic effects in pancreatic and colon cancer by suppressing the PI3K/AKT and NF-κB signaling pathways. It exerts both multiple biological or pharmacological effects and antitumor activity in various cancers, including lung, breast, and gastrointestinal tumors and so on. Melatonin (N-acetyl-5-methoxytryptamine) secreted by the endocrine pineal gland plays vital roles in modulation of circadian rhythm. However, none of them could satisfy the clinical demands due to poor response rate as single agent, which suggests urgent needs for novel therapeutic agents that could be used in combination to overcome chemoresistance effectively and safely in AML patients with FLT3-ITD mutation. It was therefore reasonable that many efforts have been made to develop novel therapeutic modality targeting FLT3-ITD and several clinical trials testing efficiency of small molecule inhibitors in AML patients are ongoing. Consequently, AML patients with FLT3-ITD mutation represent a subgroup with poor prognosis as well as intrinsic resistance to conventional chemotherapy. Constitutive internal tandem duplication (ITD) mutation of FLT3 receptors results in activation of multiple downstream pathways including MAPK, STAT and PI3K-AKT and ultimately unrestricted proliferation and cancer cells. Nearly one third of acute myeloid leukemia (AML) patients are characterized with activation mutation in the juxta membrane domain of type III receptor Fms-like tyrosine kinase 3 (FLT3). Keywords: Melatonin, Sorafenib, FLT3-ITD, Leukemia, Redox modification Introduction Importantly, combination of melatonin and sorafenib exhibited highly synergistic therapeutic activity in MV4-11 xenografts and a murine model bearing FLT3/ITD leukemia.Ĭonclusion: This study indicates that melatonin, alone or in combination with sorafenib, has potential to improve the therapeutic outcome of AML patients with FLT3-ITD mutation that merits further investigation. Moreover, melatonin significantly enhances the cytotoxicity induced by the FLT3 tyrosine kinase inhibitor sorafenib in AML cells with FLT3/ITD through redox modification. Mechanistically, melatonin preferentially causes overproduction of reactive oxygen species (ROS) and ultimately massive cell death in FLT3-ITD AML cells. Results: Our study shows for the first time that melatonin inhibits proliferation and induces apoptosis in FLT3/ITD-positive leukemia cells. Also, the ex vivo and in vivo models were used to test the synergistic effects of melatonin and sorafenib against leukemia with FLT3/ITD mutation.
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Methods: The antitumor effects of melatonin alone or combined with sorafenib were evaluated via flow cytometry and immunoblotting assays in FLT-ITD AML cells. File import instruction AbstractĪcute myeloid leukemia (AML) with an internal tandem duplication in Fms-related tyrosine kinase 3 (FLT3-ITD) is identified as a subgroup with poor outcome and intrinsic resistance to chemotherapy and therefore urgent need for development of novel therapeutic strategies.
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Available fromĬlick on Go to download the file. Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification. Pharmacological Institute of National Taiwan University College of Medicine (M.A.) from Yale University ( Gibbs Scholarship, Ph.D.Tian T, Li J, Li Y, Lu YX, Tang YL, Wang H, Zheng F, Shi D, Long Q, Chen M, Garcia-Manero G, Hu Y, Qin L, Deng W. Kaohsiung Medical University School of Pharmacy Shinchiku, Taiwan under Japanese rule (modern Hsinchu, Taiwan)