Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice.

BACKGROUND AND PURPOSE: Propranolol is a vasoactive drug that shows antiangiogenic and antitumour activities in melanoma. However, it is unknown whether these activities are dose-dependent and whether there is a relationship between systemic vascular effects of propranolol and anti-melanoma activity. EXPERIMENTAL APPROACH: Effects of increasing doses of propranolol (10, 20, 30 and 40 mg·kg-1 ·day-1 ) on tumour growth were studied in B16F10 melanoma-bearing mice. Histological and biochemical analyses were used to assess propranolol effects on angiogenesis and cancer cell proliferation. Systemic vascular resistance (SVR) was evaluated by measuring cardiac output and arterial BP. KEY RESULTS: In vitro analyses revealed that B16F10 cells expressed ß-adrenoceptors, but neither isoprenaline, a ß-adrenoceptor agonist, nor the ß-blocker propranolol affected cancer cell proliferation. In vivo studies showed that the antitumour efficacy of propranolol follows a U-shaped biphasic dose-response curve. Low doses (10 and 20 mg·kg-1 ·day-1 ) significantly inhibit tumour growth, whereas higher doses are progressively less effective. We also found that high-dose propranolol stimulates tumour arteriogenesis whereas no effect on angiogenesis was observed at any dose. Based on these data and considering that propranolol is a vasoactive drug, we hypothesized that it causes systemic vasoconstriction or vasodilation depending on the dose and thus alters tumour perfusion and growth. Consistent with this hypothesis, we found that propranolol has a biphasic effect on SVR with low and high doses producing vasoconstriction and vasodilation respectively. CONCLUSIONS AND IMPLICATIONS: Propranolol inhibits melanoma growth in a U-shaped biphasic manner. A direct relationship exists between SVR and anti-melanoma activity.