title: Dopamine blocks stress-mediated ovarian carcinoma growth.
abstract: OBJECTIVE
  Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth.
  
  
  METHODS
  Expression of dopamine receptors (DR1-DR5) was analyzed by reverse transcriptase-PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis, and migration were examined. For in vivo therapy, murine and human DR2-siRNAs were incorporated into chitosan nanoparticles (CH-NP).
  
  
  RESULTS
  In this model of chronic stress, tumoral norepinephrine levels remained elevated whereas dopamine levels were significantly decreased compared with nonstressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress-induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density as well as the stimulatory effect on apoptosis, as the DR2 antagonist eticlopride reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cyclic AMP levels and inhibited norepinephrine and vascular permeability factor/VEGF-induced Src kinase activation.
  
  
  CONCLUSIONS
  Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement.
authors.affiliation: Departments of Gynecologic Oncology, Cancer Biology, and Experimental Therapeutics, and Center for RNA Interference and Non-coding RNA, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Myrthala
authors.initials: M
authors.lastname: Moreno-Smith
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Guillermo N Armaiz
authors.initials: GN
authors.lastname: Pena
authors.forename: Julie K
authors.initials: JK
authors.lastname: Allen
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Donna
authors.initials: D
authors.lastname: Farley
authors.forename: Gabriel Lopez
authors.initials: GL
authors.lastname: Berestein
authors.forename: Steve W
authors.initials: SW
authors.lastname: Cole
authors.forename: Susan K
authors.initials: SK
authors.lastname: Lutgendorf
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004298:Dopamine / Q000096:biosynthesis / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D011954:Receptors, Dopamine / Q000096:biosynthesis / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects*; D059016:Tumor Microenvironment
chemical_list: D011954:Receptors, Dopamine; D004298:Dopamine