Beta 2 Adrenergic Receptor Antagonist Propranolol and Opioidergic Receptor Antagonist Naltrexone Produce Synergistic Effects on Breast Cancer Growth Prevention by Acting on Cancer Cells and Immune Environment in a Preclinical Model of Breast Cancer

SIMPLE SUMMARY: Here, we show that propranolol, a beta blocker used to treat high blood pressure, and naltrexone, an opiate antagonist used for drug and alcohol dependence, when combined, produce marked inhibitory effects on tumor growth and tumor mass while improving the survival rate, increasing NK cell activity, and reducing inflammatory cytokine levels in plasma. These antitumor effects resulted from a reduction in tumor cell proliferation, the induction of cellular apoptosis, and the prevention of epithelial–mesenchymal transition in the tumor. Our data identify a novel treatment with a combination of approved classes of drugs in preclinical breast cancer models. ABSTRACT: Cancer progression is known to be promoted by increased body stress caused by elevated beta-adrenergic and opioidergic nervous system activities. The effects of β2-adrenergic blocker propranolol (PRO) and μ-opioid receptor antagonist naltrexone (NTX) were tested using a preclinical model of human breast cancer. These drugs, individually, and more potently when combined, inhibited the cell growth and progression of breast cancer cells in vitro in cultures, and in vivo in rat xenografts. The antitumor activities of these drugs were associated with direct cell intrinsic effects, including increased cell growth arrest, elevated levels of apoptotic proteins, and reduced production of epithelial–mesenchymal transition factors by the tumor cells, as well as effects on innate immune activation and reduced inflammatory cytokine levels in plasma. These data suggest that the combined treatments of PRO and NTX produce impressive antitumor effects in the preclinical breast cancer model, and thereby may provide a new combinatorial treatment strategy with more clinical treatment modalities.