Dopamine Blocks Stress-Mediated Ovarian Carcinoma Growth

Abstract

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 real time reverse transcription-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-siRNA’s were incorporated into chitosan nanoparticles (CH). Results In this model of chronic stress, tumoral norepinephrine levels remained elevated while dopamine levels were significantly decreased compared to non-stressed 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 (MVD) as well as the stimulatory effect on apoptosis, since the DR2-antagonist eticlopride, reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cAMP levels and inhibited norepinephrine and VPF/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.

Nerve–Cancer Cell Cross-talk: A Novel Promoter of Tumor Progression

“…However, the mechanism is not resolved and it may be hypothesized that beta-blockers actually inhibit the stimulatory effect of catecholamines liberated by nerves in the tumor microenvironment. In addition, the effect of beta-blockers may also be related to the inhibition of stress, as dopamine, a stress inhibitory catecholamine has been shown to decrease ovarian cancer growth though an antiangiogenic effect (32,33). Finally, to date, only sympathetic and parasympathetic nerves have been implicated in tumor progression and the role of sensory nerves has not yet been reported.…”

Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

“…Dopamine (DA) is an important catecholamine neurotransmitter, which exerts its function in the target organs by binding to dopamine receptors (DRs), namely DR1 and DR2 (Missale et al, 1998;Tang et al, 2013). In vitro studies have indicated that DA inhibits tumor cell proliferation in ovarian cancer and Hodgkin's lymphoma (Moreno-Smith et al, 2011;Meredith et al, 2006), but it doesn't affect colon and breast cancer cells (Sarkar et al, 2008;Moreno-Smith et al, 2013;Chakroborty et al, 2004). DA has been demonstrated to retard tumor growth by inhibiting angiogenesis in several animal models, including ovarian, gastric, breast and colon cancer (Sarkar et al, 2008;Moreno-Smith et al, 2013;Chakroborty et al, 2004).…”

Importance of adrenergic pathways in women's cancers

“…Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro . Moreover, dopamine reduced cyclic AMP levels and inhibited NE and VEGF-induced Src kinase activation [35]. …”