title: High Efficiency Apoptosis Induction in Breast Cancer Cell Lines by MLN4924/2DG Co-Treatment.
abstract: 2-deoxy-D-Glucose (2DG) causes cytotoxicity in cancer cells by disrupting thiol metabolism. It is an effective component in therapeutic strategies. It targets the metabolism of cancer cells with glycolysis inhibitory activity. On the other hand, MLN4924, a newly discovered investigational small molecule inhibitor of NAE (NEDD8 activating enzyme), inactivates SCF E3 ligase and causes accumulation of its substrates which triggers apoptosis. Combination of these components might provide a more efficient approach to treatment. In this research, 2DG and MLN4924 were co-applied to breast cancer cells (MCF-7 and SKBR-3) and cytotoxic and apoptotic activity were evaluated the by Micro culture tetrazolium test (MTT), TUNEL and ELISA methods. Caspase3 and Bcl2 genes expression were evaluated by real time Q-PCR methods. The results showed that MLN4924 and MLN4924/2DG dose-dependently suppressed the proliferation of MCF7 and SKBR-3 cells. Cell survival of breast cancer cells exposed to the combination of 2DG/MLN4924 was decreased significantly compared to controls (p<0.05), while 2DG and MLN4924 alone had less pronounced effects on the cells. The obtained results suggest that 2DG/MLN4924 is much more efficient in breast cancer cell lines with enhanced cytotoxicity via inducing a apoptosis cell signaling gene, caspase-3.
authors.affiliation: Cellular and Molecular Biology Research Center, Medical Physics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran E-mail : pirayeshj@gmail.com.
authors.forename: Maryam
authors.initials: M
authors.lastname: Oladghaffari
authors.forename: Jalil Pirayesh
authors.initials: JP
authors.lastname: Islamian
authors.forename: Behzad
authors.initials: B
authors.lastname: Baradaran
authors.forename: Ali Shabestani
authors.initials: AS
authors.lastname: Monfared
authors.forename: Alireza
authors.initials: A
authors.lastname: Farajollahi
authors.forename: Dariush
authors.initials: D
authors.lastname: Shanehbandi
authors.forename: Mohsen
authors.initials: M
authors.lastname: Mohammadi
mesh_terms: D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors
chemical_list: D000963:Antimetabolites; D003517:Cyclopentanes; D011743:Pyrimidines; D012333:RNA, Messenger; D003847:Deoxyglucose; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat