Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma

Abstract

Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective β-adrenergic receptor antagonist propranolol hydrochloride.Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the β2, and not β1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express β2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB.

Anesthetic Considerations for Management of Cancer Patients to Decrease Cancer Recurrence

“…Inhibiting β-adrenergic signaling to pancreatic cancer cells induced apoptosis by suppressing the Ras/Akt/ NFκB signaling pathway [47,48]. Similar findings were also reported in studies of hemangioma, neuroblastoma, melanoma and gastric cancer [49][50][51][52]. Chang et al go as far as to support the use of β-blockers as a possible novel therapeutic intervention, but that claim must be utilized with caution, as recent studies by Wang et al stated that B2 adrenergic stimulation with norepinephrine has actually attenuated invasion of certain types of breast CA's migration [53].…”

Epinephrine Stimulates Cell Proliferation and Induces Chemoresistance in Myeloma Cells through the β-Adrenoreceptor in vitro

“…Although an antimyeloma effect was first reported last year [11], the antitumor effect is consistent with results obtained with other solid-tumor models including breast cancer, acute leukemia, neuroblastoma, etc. [4,10,15,16]. Even though most MM diagnoses are made in the aging population, which has a greater incidence of cardiovascular diseases, selective β-blockers are prescribed much more frequently than propranolol.…”

A balancing act: orchestrating amino-truncated and full-length p73 variants as decisive factors in cancer progression

“…C35 and ΔNp73 colocalize at peri-nuclear region, suggesting a transcriptional-independent mechanism of NFκB and AKT activation. EGCG (epigallocatechin-3-gallate ) Upregulation of TAp73 expression [187][188][189] Red wine polyphenol Upregulation of TAp73 expression 190 Arsenic trioxide Upregulation of TAp73 expression 191,192 T-oligo Oligonucleotides homologous to the 3′-telomere overhang; upregulation of TAp73 expression 167,193,194 Propranolol Nonselective β-adrenergic receptor antagonist; upregulation of TAp73 expression 195 Melphalan Upregulation of TAp73 expression 196 Sodium butyrate Histone deacetylase inhibitor; upregulation of TAp73 expression 197 7-hydroxy-staurosporine Upregulation of TAp73 expression 197 Hydroxyurea DNA replication inhibitor; upregulation of TAp73 expression 198 Aphidicolin DNA polymerase α inhibitor; upregulation of TAp73 expression 198 Resveratrol DNA replication inhibitor; upregulation of TAp73 expression 198 4-propoxyphenol DNA replication inhibitor; upregulation of TAp73 expression 198 Celecoxib COX-2 inhibitor; upregulation of TAp73 and reduction of DNp73 expression 9,199 Tazarotene Upregulation of TAp73 and reduction of DNp73 expression 200 Interferon (IFN)α Reduction of DNp73 expression 201 …”