title: Molecular target therapy of AKT and NF-kB signaling pathways and multidrug resistance by specific cell penetrating inhibitor peptides in HL-60 cells.
abstract: BACKGROUND
  PI3/AKT and NF-kB signaling pathways are constitutively active in acute myeloid leukemia and cross-talk between the two has been shown in various cancers. However, their role in acute myeloid leukemia has not been completely explored. We therefore used cell penetrating inhibitor peptides to define the contributions of AKT and NF-kB to survival and multi drug resistance (MDR) in HL-60 cells.
  
  
  METHODS
  Inhibition of AKT and NF-kB activity by AKT inhibitor peptide and NBD inhibitor peptide, respectively, resulted in decreased expression of mRNA for the MDR1 gene as assessed by real time PCR. In addition, treatment of HL-60 cells with AKT and NBD inhibitor peptides led to inhibition of cell viability and induction of apoptosis in a dose dependent manner as detected by flow cytometer.
  
  
  RESULTS
  Finally, co-treatment of HL-60 cells with sub-optimal doses of AKT and NBD inhibitor peptides led to synergistic apoptotic responses in AML cells.
  
  
  CONCLUSIONS
  These data support a strong biological link between NF-kB and PI3-kinase/AKT pathways in the modulation of anti- apoptotic and multi drug resistant effects in AML cells. Synergistic targeting of these pathways using NF-kB and PI3-kinase/AK inhibitor peptides may have a therapeutic potential for AML and possibly other malignancies with constitutive activation of these pathways.
authors.affiliation: Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran E-mail : Zarghami@tbzmed.ac.ir.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Davoudi
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Akbarzadeh
authors.forename: Mohammad
authors.initials: M
authors.lastname: Rahmatiyamchi
authors.forename: Ali Akbar
authors.initials: AA
authors.lastname: Movassaghpour
authors.forename: Mohsen
authors.initials: M
authors.lastname: Alipour
authors.forename: Kazem
authors.initials: K
authors.lastname: Nejati-Koshki
authors.forename: Zohre
authors.initials: Z
authors.lastname: Sadeghi
authors.forename: Hassan
authors.initials: H
authors.lastname: Dariushnejad
authors.forename: Nosratollah
authors.initials: N
authors.lastname: Zarghami
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D057846:Cell-Penetrating Peptides; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt