title: Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Propranolol inhibits melanoma growth in a U-shaped biphasic manner. A direct relationship exists between SVR and anti-melanoma activity.
authors: Department of Pharmacology, National Institute of Health, Rome, Italy.
authors: Sonia
authors: S
authors: Maccari
authors: Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy.
authors: Maria
authors: M
authors: Buoncervello
authors: Cell Biology and Neurobiology Institute, CNR, Rome, Italy.
authors: Andrea
authors: A
authors: Rampin
authors: Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy.
authors: Massimo
authors: M
authors: Spada
authors: Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy.
authors: Daniele
authors: D
authors: Macchia
authors: Department of Pharmacology, National Institute of Health, Rome, Italy.
authors: Luciana
authors: L
authors: Giordani
authors: Department of Pharmacology, National Institute of Health, Rome, Italy.
authors: Tonino
authors: T
authors: Stati
authors: Cell Biology and Neurobiology Institute, CNR, Rome, Italy.
authors: Claudia
authors: C
authors: Bearzi
authors: National Blood Center, Rome, Italy.
authors: Liviana
authors: L
authors: Catalano
authors: Cell Biology and Neurobiology Institute, CNR, Rome, Italy.
authors: Roberto
authors: R
authors: Rizzi
authors: Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy.
authors: Lucia
authors: L
authors: Gabriele
authors: Department of Pharmacology, National Institute of Health, Rome, Italy.
authors: Giuseppe
authors: G
authors: Marano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011433:Propranolol / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011433:Propranolol