Clinical Use of Propranolol Reduces Biomarkers of Proliferation in Gastric Cancer

Abstract

Gastric cancer has one of the highest mortality rate in the world, but the treatment is still limited. Building on previous studies, mechanistic studies on propranolol in gastric cancer mice models and gastric cancer patients were performed. Propranolol inhibited the in vitro proliferation of gastric cancer cells in a time- and concentration-dependent manner. Consistent findings were observed in MFC tumors engrafted 615 mice, which were treated with propranolol at 10 mg/kg daily for 14 days. Propranolol inhibited the phosphorylation of AKT, MEK, and ERK proteins than control in mice tumor tissues respectively (p-AKT 26.16 vs. 56.82, P = 0.0196, p-MEK 28.27 vs. 59.28, P = 0.1102, p-ERK 48.2 vs. 107.4, P = 0.0062). Propranolol had antiproliferative activity in gastric cancer patients receiving 60 mg daily for 7 days prior to surgery(ki67 44.8 vs 125.3 for placebo; P = 0.02). Phosphorylated AKT, MEK, and ERK did not differ between propranolol and placebo treatment in gastric cancer patients. The expression of molecules on CD8+ T cells was not changed both in mice model and patients nor was there a statistically significant difference in CD8+ T cell subsets in patients, although suggestion of an effect was evident. These results prove that propranolol may inhibit the growth of gastric cancer in mice model and patients and the possible mechanism was via inhibiting the AKT and MAPK pathways, but the frequency of tumor infiltration CD8+ T cells did not increase significantly.

Adrenergic receptor signaling regulates the CD40-receptor mediated anti-tumor immunity

“…Retrieved from https://app.biorender.com/biorender-templates. (64)(65)(66)(67)(68). Future studies may include PBS (or an isotype control antibody) to further confirm the feasibility of the proposed combination therapy in the MOC2 murine model.…”

Harnessing interventions during the immediate perioperative period to improve the long-term survival of patients following radical gastrectomy

“…In vitro studies, propranolol, the most commonly used nonselective-adrenergic antagonist, showed the ability to induce apoptosis, repress growth, suppress the expression of matrix metalloproteinases and vascular endothelial growth factor, and inhibit the migration of GC cells[ 38 , 39 ]. In a xenograft mouse model, propranolol decreased the levels of phosphorylated AKT, MEK, and ERK proteins and blocked depression-promoted neuroendocrine phenotypic transformation and lung metastasis of GC[ 31 , 40 , 41 ]. In patients with GC, treatment with propranolol for one week before surgery significantly inhibited the proliferation of cancer, as measured by Ki-67[ 40 ].…”

“…In a xenograft mouse model, propranolol decreased the levels of phosphorylated AKT, MEK, and ERK proteins and blocked depression-promoted neuroendocrine phenotypic transformation and lung metastasis of GC[ 31 , 40 , 41 ]. In patients with GC, treatment with propranolol for one week before surgery significantly inhibited the proliferation of cancer, as measured by Ki-67[ 40 ]. In other cancer types, the anticancer ability of propranolol has also been found to be associated with enhanced antitumor immunity[ 42 , 43 ].…”

“…In other cancer types, the anticancer ability of propranolol has also been found to be associated with enhanced antitumor immunity[ 42 , 43 ]. However, this effect was not observed in GC animal models or patients[ 40 ]. Based on the findings of preclinical studies, several clinical trials have been carried out to assess the effects of perioperative β-blockers on oncological outcomes, but none of them have been designed to focus on survival.…”

Emerging Roles of the Nervous System in Gastrointestinal Cancer Development

“…Despite the fact that denervation exhibits considerable merit in preventing tumor progression, the potential side-effects may hinder its translation into clinical practice. On the other hand, pharmacological inhibition of neural receptors appears to be a reliable intervention that may be applied into clinical use [ 252 , 253 ]. Coinciding with the presumed tumor-facilitating role of β-AR signaling, epidemiological studies revealed that administration of β-blockers, such as propranolol, may reduce GI cancer risk [ 254 , 255 , 256 ].…”