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
β-adrenoceptors, but neither isoprenaline, a β-adrenoceptor agonist, nor the
β-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.