Dopamine Blocks Stress-Mediated Ovarian Carcinoma Growth

• Published in: Clinical cancer research 2011-06, Vol.17 (11), p.3649-3659
• Main Authors: MORENO-SMITH, Myrthala, CHUNHUA LU, LOPEZ BERESTEIN, Gabriel, COLE, Steve W, LUTGENDORF, Susan K, SOOD, Anil K, SHAHZAD, Mian M. K, ARMAIZ PENA, Guillermo N, ALLEN, Julie K, STONE, Rebecca L, MANGALA, Lingegowda S, HEE DONG HAN, HYE SUN KIM, FARLEY, Donna
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Catecholamines; Cell Line, Tumor; Cell migration; Cell Proliferation - drug effects; chitosan; Cyclic AMP; Dopamine; Dopamine - biosynthesis; Dopamine - pharmacology; Dopamine receptors; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Immunodeficiency; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Nude; Microenvironments; nanoparticles; Neovascularization, Pathologic; Norepinephrine; Ovarian carcinoma; Ovarian Neoplasms - blood supply; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Receptors, Dopamine - biosynthesis; Receptors, Dopamine - genetics; Src protein; Stress; Stress, Physiological - drug effects; Tumor Microenvironment; Tumors; Vascular permeability factor; Western blotting
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-2441

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. 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). 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. Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement.