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, R. Rizzi, Lucia Gabriele, Giuseppe Marano

Research output: Contribution to journalArticle

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 pages10
JournalBritish Journal of Pharmacology
Volume174
Publication statusPublished - Jan 2017

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Propranolol
Melanoma
Growth
Neoplasms
Vasodilation
Adrenergic Receptors
Cell Proliferation
Vasoconstriction
Isoproterenol
Cardiac Output
Antineoplastic Agents
Blood Vessels
Perfusion
Pharmaceutical Preparations

Keywords

  • Melanoma

Cite this

Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice. / Maccari, Sonia; Buoncervello, Maria; Rampin, Andrea; Spada, Massimo; Macchia, Daniele; Giordani, Luciana; Stati, Tonino; Bearzi, Claudia; Catalano, Liviana; Rizzi, R.; Gabriele, Lucia; Marano, Giuseppe.

In: British Journal of Pharmacology, Vol. 174, 01.2017, p. 139-149.

Research output: Contribution to journalArticle

Maccari, S, Buoncervello, M, Rampin, A, Spada, M, Macchia, D, Giordani, L, Stati, T, Bearzi, C, Catalano, L, Rizzi, R, Gabriele, L & Marano, G 2017, 'Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice.', British Journal of Pharmacology, vol. 174, pp. 139-149.
Maccari, Sonia ; Buoncervello, Maria ; Rampin, Andrea ; Spada, Massimo ; Macchia, Daniele ; Giordani, Luciana ; Stati, Tonino ; Bearzi, Claudia ; Catalano, Liviana ; Rizzi, R. ; Gabriele, Lucia ; Marano, Giuseppe. / Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice. In: British Journal of Pharmacology. 2017 ; Vol. 174. pp. 139-149.
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T1 - Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice.

AU - Maccari, Sonia

AU - Buoncervello, Maria

AU - Rampin, Andrea

AU - Spada, Massimo

AU - Macchia, Daniele

AU - Giordani, Luciana

AU - Stati, Tonino

AU - Bearzi, Claudia

AU - Catalano, Liviana

AU - Rizzi, R.

AU - Gabriele, Lucia

AU - Marano, Giuseppe

PY - 2017/1

Y1 - 2017/1

N2 - BACKGROUND AND PURPOSE: Propranolol is a vasoactive drug that showsantiangiogenic and antitumour activities in melanoma. However, it is unknownwhether these activities are dose-dependent and whether there is a relationshipbetween systemic vascular effects of propranolol and anti-melanoma activity.EXPERIMENTAL APPROACH: Effects of increasing doses of propranolol (10, 20, 30 and40 mg·kg-1 ·day-1 ) on tumour growth were studied in B16F10 melanoma-bearingmice. Histological and biochemical analyses were used to assess propranololeffects on angiogenesis and cancer cell proliferation. Systemic vascularresistance (SVR) was evaluated by measuring cardiac output and arterial BP.KEY RESULTS: In vitro analyses revealed that B16F10 cells expressedβ-adrenoceptors, but neither isoprenaline, a β-adrenoceptor agonist, nor theβ-blocker propranolol affected cancer cell proliferation. In vivo studies showed that the antitumour efficacy of propranolol follows a U-shaped biphasicdose-response curve. Low doses (10 and 20 mg·kg-1 ·day-1 ) significantly inhibit tumour growth, whereas higher doses are progressively less effective. We alsofound that high-dose propranolol stimulates tumour arteriogenesis whereas noeffect on angiogenesis was observed at any dose. Based on these data andconsidering that propranolol is a vasoactive drug, we hypothesized that it causessystemic vasoconstriction or vasodilation depending on the dose and thus alterstumour perfusion and growth. Consistent with this hypothesis, we found thatpropranolol has a biphasic effect on SVR with low and high doses producingvasoconstriction and vasodilation respectively.CONCLUSIONS AND IMPLICATIONS: Propranolol inhibits melanoma growth in a U-shaped biphasic manner. A direct relationship exists between SVR and anti-melanomaactivity.

AB - BACKGROUND AND PURPOSE: Propranolol is a vasoactive drug that showsantiangiogenic and antitumour activities in melanoma. However, it is unknownwhether these activities are dose-dependent and whether there is a relationshipbetween systemic vascular effects of propranolol and anti-melanoma activity.EXPERIMENTAL APPROACH: Effects of increasing doses of propranolol (10, 20, 30 and40 mg·kg-1 ·day-1 ) on tumour growth were studied in B16F10 melanoma-bearingmice. Histological and biochemical analyses were used to assess propranololeffects on angiogenesis and cancer cell proliferation. Systemic vascularresistance (SVR) was evaluated by measuring cardiac output and arterial BP.KEY RESULTS: In vitro analyses revealed that B16F10 cells expressedβ-adrenoceptors, but neither isoprenaline, a β-adrenoceptor agonist, nor theβ-blocker propranolol affected cancer cell proliferation. In vivo studies showed that the antitumour efficacy of propranolol follows a U-shaped biphasicdose-response curve. Low doses (10 and 20 mg·kg-1 ·day-1 ) significantly inhibit tumour growth, whereas higher doses are progressively less effective. We alsofound that high-dose propranolol stimulates tumour arteriogenesis whereas noeffect on angiogenesis was observed at any dose. Based on these data andconsidering that propranolol is a vasoactive drug, we hypothesized that it causessystemic vasoconstriction or vasodilation depending on the dose and thus alterstumour perfusion and growth. Consistent with this hypothesis, we found thatpropranolol has a biphasic effect on SVR with low and high doses producingvasoconstriction and vasodilation respectively.CONCLUSIONS AND IMPLICATIONS: Propranolol inhibits melanoma growth in a U-shaped biphasic manner. A direct relationship exists between SVR and anti-melanomaactivity.

KW - Melanoma

M3 - Article

VL - 174

SP - 139

EP - 149

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

ER -