medwireNews: Early data point to an antitumor role for the beta blocker carvedilol in patients with nonmetastatic breast cancer.
The breast cancer-specific mortality rate was lower among patients who were versus were not taking carvedilol at the time of diagnosis, report Erica Sloan (Monash University, Melbourne, Victoria, Australia) and collaborators, who also share in vitro and in vivo data indicating the antitumor activity of the beta blocker.
“These findings provide a rationale to further explore the use of the β-blocker carvedilol as a novel strategy to slow cancer progression,” the team writes in the European Journal of Cancer.
The study authors explain that the sympathetic nervous system-induced “[a]ctivation of β-adrenergic receptors within tumour cells drives a signaling cascade that modulates expression of genes involved in epithelial-mesenchymal transition and invasion, immunosuppression and vasculature remodelling.”
Therefore, drugs that block signaling via these receptors – such as the third-generation, nonselective, beta blocker carvedilol currently used for the management of cardiovascular disorders and chemotherapy-induced cardiotoxicity – are being investigated as anticancer therapeutics, they say.
Using data from linked Norwegian databases, the researchers identified 4014 women aged 55 years or older who were diagnosed with stage I–III breast cancer in 2007–2017 and were using antihypertensive medications (excluding beta blockers other than carvedilol).
Over a median follow-up of 5.5 years, the 5-year cumulative incidence of breast cancer deaths was 3.1% among the 136 participants who were taking carvedilol at the time of diagnosis and was 5.7% for the remaining 3878 women who were not prescribed the beta blocker.
“The association between carvedilol use and reduced breast cancer–specific mortality was statistically significant in univariate analysis and borderline statistically significant after adjusting for cancer stage and other factors,” say Sloan et al.
They also used the human breast cancer cell line MDA-MB-231HM and the mouse breast cancer cell line 4T1.2 to show that treatment with carvedilol 1 μM “effectively blocked” the isoprenaline-induced invasion of tumor cells through an extracellular matrix.
And in a mouse model generated by injecting animals with MDA-MB-231HM tumor cells, administration of carvedilol 2 mg/kg was associated with a significant reduction in the growth of the primary tumor and metastases relative to the use of the vehicle control.
Of note, this reduction in tumor growth with carvedilol was observed only in mice whose sympathetic nervous system had been activated by repeated restraint stress and not in animals that had not been subjected to such stress.
These results “suggest that carvedilol may be most effective in cancer in the context of stress, wherein elevated sympathetic nervous system activity drives β-adrenergic signaling,” remark Sloan and colleagues.
They continue: “Thus, carvedilol may have the most beneficial effect in patients with heightened anxiety, both to slow cancer progression and for anxiety management.
“However, it would be important to evaluate the effect of carvedilol in all patients as a recent randomised trial of the β-blocker propranolol found decreased expression of mesenchymal genes in all patients treated with propranolol, regardless of whether propranolol treatment induced clinical evidence of β-blockade (i.e. heart rate and blood pressure reduction).”
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