title: Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment.
abstract: Recent clinical evidence revealed that the use of beta-blockers such as propranolol, prior to diagnosis or concurrently with chemotherapy, could increase relapse-free and overall survival in breast cancer patients. We therefore hypothesized that propranolol may be able to increase the efficacy of chemotherapy either through direct effects on cancer cells or via anti-angiogenic mechanisms. In vitro proliferation assay showed that propranolol (from 50-100 μM) induces dose-dependent anti-proliferative effects in a panel of 9 human cancer and "normal" cell lines. Matrigel assays revealed that propranolol displays potent anti-angiogenic properties at non-toxic concentrations (less than 50 μM) but exert no vascular-disrupting activity. Combining chemotherapeutic drugs, such as 5-fluorouracil (5-FU) or paclitaxel, with propranolol at the lowest effective concentration resulted in synergistic, additive or antagonistic effects on cell proliferation in vitro depending on the cell type and the dose of chemotherapy used. Interestingly, breast cancer and vascular endothelial cells were among the most responsive to these combinations. Furthermore, Matrigel assays indicated that low concentrations of propranolol (10 - 50 μM) potentiated the anti-angiogenic effects of 5-FU and paclitaxel. Using an orthotopic xenograft model of triple-negative breast cancer, based on s.c injection of luciferase-expressing MDA-MB-231 cells in the mammary fat pad of nude mice, we showed that propranolol, when used alone, induced only transient anti-tumor effects, if at all, and did not increase median survival. However, the combination of propranolol with chemotherapy resulted in more profound and sustained anti-tumor effects and significantly increased the survival benefits induced by chemotherapy alone (+19% and +79% in median survival for the combination as compared with 5-FU alone and paclitaxel alone, respectively; p less than 0.05). Collectively our results show that propranolol can potentiate the anti-angiogenic effects and anti-tumor efficacy of chemotherapy. The current study, together with retrospective clinical data, strongly suggests that the use of propranolol concurrently with chemotherapy may improve the outcome of breast cancer patients, thus providing a strong rationale for the evaluation of this drug combination in prospective clinical studies.
authors: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia. epasquier@ccia.unsw.edu.au
authors: Eddy
authors: E
authors: Pasquier
authors: Joseph
authors: J
authors: Ciccolini
authors: Manon
authors: M
authors: Carre
authors: Sarah
authors: S
authors: Giacometti
authors: Raphaelle
authors: R
authors: Fanciullino
authors: Charlotte
authors: C
authors: Pouchy
authors: Marie-Pierre
authors: MP
authors: Montero
authors: Cindy
authors: C
authors: Serdjebi
authors: Maria
authors: M
authors: Kavallaris
authors: Nicolas
authors: N
authors: André
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use; D011433:Propranolol / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011433:Propranolol; D017239:Paclitaxel; D005472:Fluorouracil