Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment.
, Ciccolini J
, Carre M
, Giacometti S
, Fanciullino R
, Pouchy C
, Montero MP
, Serdjebi C
, Kavallaris M
, André N
Free PMC Article
Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia. firstname.lastname@example.org
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.
- [PubMed - indexed for MEDLINE]
Our study first demonstrated that propranolol has relatively modest anti-proliferative properties in vitro against a panel of 9 human cell lines. High concentrations of propranolol were required to significantly inhibit cell proliferation, with IC50 values ranging from 100 μM to >250 μM across the panel of cell lines. Early pharmacokinetics studies revealed that clinically relevant concentrations of propranolol are in the low μM range [35, 36], thus suggesting that propranolol alone is not likely to inhibit cell proliferation in vivo. The sensitivity to propranolol was cell type specific but did not depend on the tissue of origin, since all 4 cell lines of breast tissue origin displayed different levels of sensitivity. Interestingly, MCF-7 breast cancer cells were twice as much sensitive to propranolol than MDA-MB-231 cells, although the former have been reported to express low levels of β-ARs as compared to the latter . This suggests that the level of β-AR expression may not directly influence cell sensitivity to the anti-proliferative effect of propranolol. In contrast with its modest effects on cell proliferation, propranolol was able to significantly inhibit angiogenesis in vitro at relatively low concentrations (from 10 and 20 μM in BMH29L and HMEC-1 cells, respectively).
Triple-negative breast cancer is estimated to affect more than 170,000 women worldwide each year and associated with a poor prognosis . Effective therapeutic options are very limited but β-AR antagonists have been recently found to be particularly beneficial in triple-negative breast cancer patients .
A Retrospective In Vitro Study of the Impact of Anti-diabetics and Cardioselective Pharmaceuticals on Breast Cancer.
, Richter C
, Briese V
, Richter DU
Department of Obstetrics and Gynecology, University of Rostock, Südring 81, D-18059 Rostock, Germany. email@example.com
In a retrospective controlled study, a tumor-protective effect, regarding breast cancer, was determined for the medicines metformin and glitazone (anti-diabetics), bisoprolol, and propranolol (cardioselective β1 adrenoceptor antagonists). Our main goal was to provide evidence, showing the tumor-protective effects of beta-blockers and of antidiabetics via investigations in vitro.
MATERIALS AND METHODS:
Four different medicines were tested in cell cultures: Propranolol: 2.4 mg/ml and 0.3 mg/ml; bisoprolol: 0.1 mg/ml and 0.05 mg/ml; metformin: 7.5 mg/ml, 2.5 mg/ml, and 0.15 mg/ml; and glitazone: 2.5 mg/ml, 0.15 mg/ml, and 0.05 mg/ml. The human breast cancer cell lines MCF7 and BT20 (estrogen receptor-positive and -negative
; ATCC; cell density: 5×10(5) cells/ml) were used. Both cell lines were cultured under sterile conditions in incubators at 37°C, with a humidified atmosphere of 5% CO(2). The influences of the drugs were determined through cytotoxicity and proliferation assays and performance of a hydrogen peroxide assay. Morphological observations (light microscopy) and metabolic investigations (pH value, glucose) were also performed.
The application of the beta-blocker propranolol resulted in highly cytotoxic effects (>90%) in both cell lines
. In contrast, bisoprolol did not have any effects, neither in cytotoxicity tests nor in cell proliferation assays. The anti-diabetic metformin had a higher cytotoxic influence on the BT20 than did on the MCF7 cell line. The cell proliferation of BT20 was significantly inhibited after the addition of 2.5 mg/ml metformin and of 2.5 mg/ml glitazone
. The application of glitazone also resulted in an increase of hydrogen peroxide and a decrease of the pH value.
The strongest cytotoxic effect was observed with propranolol
suggesting that, in clinical practice, this pharmaceutical can be used in patients with breast cancer who have hypertension. A specific clinical recommendation for anti-diabetics is not yet possible.
- [PubMed - in process]
Used off label for stage fright and PTSD: LINK
J Clin Oncol.
2011 Jul 1;29(19):2635-44. Epub 2011 May 31.
Beta blockers and breast cancer mortality: a population- based study.
, Connolly RM
, Sharp L
, Bennett K
, Visvanathan K
Trinity College, University of Dublin, Dublin, Ireland. firstname.lastname@example.org
Preclinical studies have demonstrated that antagonism of β₂-adrenergic signaling inhibits several pathways necessary for breast tumor progression and metastasis. A series of population-based observational studies were conducted to examine associations between beta blocker use and breast tumor characteristics at diagnosis or breast cancer-specific mortality.
PATIENTS AND METHODS:
Linked national cancer registry and prescription dispensing data were used to identify women with a diagnosis of stage I to IV invasive breast cancer between January 1, 2001, and December 31, 2006. Women taking propranolol (β₁/β₂ antagonist; n = 70) or atenolol (β₁ antagonist; n = 525), in the year before breast cancer diagnosis were matched (1:2) to women not taking a beta blocker (n = 4,738). Associations between use of propranolol or atenolol and risk of local tumor invasion at diagnosis (T4 tumor), nodal or metastatic involvement at diagnosis (N2/N3/M1 tumor), and time to breast cancer-specific mortality were assessed.
Propranolol users were significantly less likely to present with a T4
(odds ratio [OR], 0.24, 95% CI, 0.07 to 0.85) or N2/N3/M1 (OR, 0.20; 95% CI, 0.04 to 0.88) tumor compared with matched nonusers. The cumulative probability of breast cancer-specific mortality was significantly lower for propranolol users
compared with matched nonusers (hazard ratio, 0.19; 95% CI, 0.06 to 0.60). There was no difference in T4 or N2/N3/M1 tumor incidence or breast cancer-specific mortality between atenolol users and matched nonusers.
The results provide evidence in humans to support preclinical observations suggesting that inhibiting the β₂-adrenergic signaling pathway can reduce breast cancer progression and mortality.
- [PubMed - indexed for MEDLINE]
Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival.
, Voss MJ
, Zänker KS
, Habashy HO
, Green AR
, Ellis IO
, Entschladen F
Free PMC Article
Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, UK. email@example.com
Laboratory models show that the beta-blocker, propranolol, can inhibit norepinephrine-induced breast cancer cell migration. We hypothesised that breast cancer patients receiving beta-blockers for hypertension would show reduced metastasis and improved clinical outcome.
Three patient subgroups were identified from the medical records of 466 consecutive female patients (median age 57, range 28-71) with operable breast cancer and follow-up (>10 years). Two subgroups comprised 43 and 49 hypertensive patients treated with beta-blockers or other antihypertensives respectively, prior to cancer diagnosis. 374 patients formed a non-hypertensive control group. Metastasis development, disease free interval, tumour recurrence and hazards risk were statistically compared between groups. Kaplan-Meier plots were used to model survival and DM. Beta-blocker treated patients showed a significant reduction in metastasis development (p=0.026), tumour recurrence (p=0.001), and longer disease free interval (p=0.01). In addition, there was a 57% reduced risk of metastasis (Hazards ratio=0.430; 95% CI=0.200-0.926, p=0.031), and a 71% reduction in breast cancer mortality after 10 years (Hazards ratio=0.291; 95% CI=0.119-0.715, p=0.007). This proof-of-principle study showed beta-blocker therapy significantly reduces distant metastases, cancer recurrence, and cancer-specific mortality in breast cancer patients suggesting a novel role for beta-blocker therapy.
A larger epidemiological study leading to randomised clinical trials is needed for breast and other cancer types including colon, prostate and ovary.
- [PubMed - indexed for MEDLINE]