beta-Adrenoreceptor antagonists reduce cancer cell proliferation, invasion, and migration

İşeri, Özlem Darcansoy; Şahin, Feride İffet; Terzi, Yunus Kasım; Yurtçu, Erkan; Erdem, Remzi; Sarıalıoğlu, Faık

doi:10.3109/13880209.2014.892513

Cited by 47 publications

(40 citation statements)

References 37 publications

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“…2). These results appear to be consistent with those of preclinical studies suggesting that the effects of beta-adrenergic signaling on tumor progression and metastasis are inhibited by the β2-receptor antagonists but not by β1 antagonists [18–24]. Consequently, better designed observational studies or randomized controlled trials are required before this type of beta-blocker can be considered as a therapeutic option for patients with breast cancer.…”

Section: Discussionsupporting

confidence: 86%

“…Some studies has demonstrated that beta-2 adrenergic signaling plays a role in several pathways involved in breast tumor progression and metastasis [17, 18], but others have found that beta-adrenergic receptor (AR) stimulation may both inhibit and promote breast tumor growth [19–23]. A recently published study adds further to the body of evidence on the effect of agonist type, indicating that the beta 2-AR antagonist in particular seems to be the most cytotoxic beta-blocker in non-stimulated cancer cells [24]. However, the majority of clinical observational studies carried out to date have focused on comparing the association between the use of propranolol or atenolol and breast cancer risk or mortality and have not explored the relationship between the subtype of beta-AR expression and breast cancer risk [25, 26].…”

Section: Discussionmentioning

confidence: 99%

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Long-Term Use of Antihypertensive Agents and Risk of Breast Cancer: A Population-Based Case–Control Study

et al. 2015

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IntroductionTo evaluate the risk of breast cancer associated with long-term use of antihypertensive agents (AHs) in Taiwanese women with hypertension.MethodsA search of the Taiwan National Health Insurance Research Database identified 330,699 patients with hypertension who were treated with antihypertensive drugs between January 1, 1998 and December 31, 2011. Logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) between the use of AHs and breast cancer risk, adjusted for other types of antihypertensive drugs, statins and co-morbidities.ResultsAmong the AHs used to treat the hypertensive women enrolled in our study, our analysis revealed that those treated with one specific particular class of beta-blockers (beta-1 selective beta-blockers) had an increased risk for breast cancer. We also found that the ever-use of calcium channel blockers (CCBs; i.e. for 13 years) was associated with breast cancer in an adjusted model (OR 1.09; 95% CI 1.03–1.16). However, the use of nonselective beta-blockers, selective and nonselective alpha-blockers, angiotensin-converting enzyme inhibitors and angiotensin II antagonists were not associated with breast cancer risk.ConclusionBased on the results of our analysis, long-term use of CCBs or beta-1 selective beta-blockers are likely to be associated with the risk of breast cancer. Further large comprehensive population-based studies to support our findings are required for confirmation of this conclusion.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Long-Term Use of Antihypertensive Agents and Risk of Breast Cancer: A Population-Based Case–Control Study

et al. 2015

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“…In a comparison between PRO and the selective beta adrenergic receptor antagonists atenolol (beta1) and ICI118-551 (beta 2), Işeri and colleagues showed that PRO and ICI118,551 were more potent in reducing the proliferation, migration, and invasion of non-stimulated breast (MCF7), colon (HT-29), and hepatocellular (HepG2) cancer cells than atenolol [101]. …”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…In contrast, there have also been contradictory results, for example for breast cancer where Pérez Piñero et al have reported that beta adrenergic agonists isoprenaline and salbutamol reduced breast tumour growth in animal models, and that PRO treatment reversed this inhibition [102] and other authors have reported a decrease in proliferation in breast cancer cell line, for example in the MCF7 cell line [101]. …”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

Pantziarka

Bouche

Sukhatme³

et al. 2016

ecancer

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Propranolol (PRO) is a well-known and widely used non-selective beta-adrenergic receptor antagonist (beta-blocker), with a range of actions which are of interest in an oncological context. PRO displays effects on cellular proliferation and invasion, on the immune system, on the angiogenic cascade, and on tumour cell sensitivity to existing treatments. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. In particular there is evidence that PRO is effective at multiple points in the metastatic cascade, particularly in the context of the post-surgical wound response. Based on this evidence the case is made for further clinical investigation of the anticancer effects of PRO, particularly in combination with other agents. A number of trials are on-going, in different treatment settings for various cancers.

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“…Our labs have spearheaded efforts to examine the mechanism of action and clinical use of β-blockers against tumors and have reported that β-blockade disrupts proliferation, survival, migration, cell-to-matrix attachment, and global transcriptional expression patterns in vascular tumors including infantile hemangiomas and angiosarcomas [19–23]. Other labs have shown that β-AR signaling affects epithelial-to-mesenchymal transition [24] and β-blockade reduces tumor angiogenesis, cell proliferation, migration, and invasion [25–30]. Our labs and others have translated these retrospective and preclinical studies into the clinic to report that use of the β-blocker propranolol in patients with lethal angiosarcomas results in decreased tumor proliferation and sustained therapeutic responses [31–33].…”

Section: Introductionmentioning

confidence: 99%

Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer

et al. 2016

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Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.

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beta-Adrenoreceptor antagonists reduce cancer cell proliferation, invasion, and migration

Cited by 47 publications

References 37 publications

Long-Term Use of Antihypertensive Agents and Risk of Breast Cancer: A Population-Based Case–Control Study

Long-Term Use of Antihypertensive Agents and Risk of Breast Cancer: A Population-Based Case–Control Study

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer

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