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

Sonia Maccari, Maria Buoncervello, Andrea Rampin, Massimo Spada, Daniele Macchia, Luciana Giordani, Tonino Stati, Claudia Bearzi, Liviana Catalano, Roberto Rizzi, Lucia Gabriele, Giuseppe Marano

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)139-149
Number of pages11
JournalBritish Journal of Pharmacology
Volume174
Issue number2
DOIs
Publication statusPublished - Jan 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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