Human Cancer Biology Dopamine Blocks Stress-Mediated Ovarian Carcinoma Growth

Purpose: 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. Experimental Design: 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)ovariancancermodels.This increasewascompletelyblockedwithdailydopamine treatment. Dopamine treatment also blocked the stress-induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack ofDR3 expression in ovarian cancer cells.DR2was responsible for the inhibitory effectsof dopamineon tumorgrowthandmicrovesseldensity as well as the stimulatoryeffectonapoptosis, as theDR2antagonist eticlopride reversed theseeffects.Dopamine significantlyinhibitedcellviabilityandstimulatedapoptosis invitro.Moreover,dopaminereducedcyclicAMP 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. Clin Cancer Res; 17(11); 3649–59.