title: Inhibition of FoxM1-Mediated DNA Repair by Imipramine Blue Suppresses Breast Cancer Growth and Metastasis.
abstract: The approaches aimed at inhibiting the ability of cancer cells to repair DNA strand breaks have emerged as promising targets for treating cancers. Here, we assessed the potential of imipramine blue (IB), a novel analogue of antidepressant imipramine, to suppress breast cancer growth and metastasis by inhibiting the ability of breast cancer cells to repair DNA strand breaks by homologous recombination (HR).
  
  
  
  The effect of IB on breast cancer growth and metastasis was assessed in vitro as well as in preclinical mouse models. Besides, the therapeutic efficacy and safety of IB was determined in ex vivo explants from breast cancer patients. The mechanism of action of IB was evaluated by performing gene-expression, drug-protein interaction, cell-cycle, and DNA repair studies.
  
  
  
  We show that the systemic delivery of IB using nanoparticle-based delivery approach suppressed breast cancer growth and metastasis without inducing toxicity in preclinical mouse models. Using ex vivo explants from breast cancer patients, we demonstrated that IB inhibited breast cancer growth without affecting normal mammary epithelial cells. Furthermore, our mechanistic studies revealed that IB may interact and inhibit the activity of proto-oncogene FoxM1 and associated signaling that play critical roles in HR-mediated DNA repair.
  
  
  
  These findings highlight the potential of IB to be applied as a safe regimen for treating breast cancer patients. Given that FoxM1 is an established therapeutic target for several cancers, the identification of a compound that inhibits FoxM1- and FoxM1-mediated DNA repair has immense translational potential for treating many aggressive cancers. Clin Cancer Res; 22(14); 3524-36. ©2016 AACR.
authors.affiliation: Department of Cell and Structure Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Subapriya
authors.initials: S
authors.lastname: Rajamanickam
authors.affiliation: Department of Cell and Structure Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Subbarayalu
authors.initials: S
authors.lastname: Panneerdoss
authors.affiliation: Department of Cell and Structure Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Aparna
authors.initials: A
authors.lastname: Gorthi
authors.affiliation: Department of Cell and Structure Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Santosh
authors.initials: S
authors.lastname: Timilsina
authors.affiliation: Department of Cell and Structure Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Onyeagucha
authors.affiliation: Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Kovalskyy
authors.affiliation: Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Ivanov
authors.affiliation: Department of Laboratory Animal Resources, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Martha A
authors.initials: MA
authors.lastname: Hanes
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.affiliation: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Department of Epidemiology and Statistics, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cell and Structure Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Bishop
authors.affiliation: Emory School of Medicine, Atlanta, Georgia. Veterans Administration Medical Center, Atlanta, Georgia.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Department of Cell and Structure Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. raom@uthscsa.edu.
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Rao
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007099:Imipramine / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D000090063:Proto-Oncogene Mas
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D007099:Imipramine