Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8⁺ T Cells and Inhibiting Tumor AKT/MAPK Pathway

Abstract

Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8+ T‐cell–mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p‐AKT/p‐ERK/p‐MEK in tumor tissue. The frequency of tumor CD8+ T cells was significantly elevated in propranolol‐treated mice. The expression of GzmB/IFN‐γ/T‐bet in the CD8+ T‐cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol‐treated surgical specimens, the expression of p‐ERK was decreased and the frequency of CD8+ was significantly elevated. The expression of GzmB in the CD8+ T‐cell population was significantly increased in propranolol‐treated subjects. Together, these data show propranolol simultaneously activating autologous CD8+ T cells and decreasing the expression of p‐AKT/p‐ERK/p‐MEK in mouse tumor models, while inhibiting the expression of p‐ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for antitumor effect, as the activity of this old drug is moved forward.

BMPR2 expression level is correlated with low immune infiltration and predicts metastasis and poor survival in osteosarcoma

“…MAPK-mutant tumors are the only CD8+ T cell-inflamed tumors with high immunoreactivity and a constitutively cytolytic tumor microenvironment. The MAPK-mutant head and neck squamous-cell carcinoma model with immune function shows active cell death and extensive CD8+ T cell recruitment (61,62). We infer that BMPR2 regulates the immune microenvironment of osteosarcoma tissue through the MAPK/ERK pathway.…”

Clinical Use of Propranolol Reduces Biomarkers of Proliferation in Gastric Cancer

“…Liao et al. also found that propranolol inhibited colorectal cancer proliferation by regulating the AKT and MAPK pathways ( 7 ). Previous studies demonstrated that propranolol can down-regulate the expression of CyclinD1, leading to G1/S arrest ( 16 , 17 ).…”

“…In the past decade, many studies have proved that propranolol can induce apoptosis, inhibit proliferation, angiogenesis, and metastasis across solid tumors ( 2 – 6 ). Recent data suggested that propranolol suppressed colorectal cancer cell growth through simultaneously activating autologous CD8 + T cells and decreasing the phosphorylation level of mitogen-activated protein kinase (MAPK)/(ATP-dependent tyrosine kinases) AKT pathway ( 7 ). Several studies also observed that propranolol may exert an anti-tumor effect in melanoma and breast cancer by suppressing AKT and MAPK signaling pathways ( 8 ).…”

Highlighting the Potential for Chronic Stress to Minimize Therapeutic Responses to Radiotherapy through Increased Immunosuppression and Radiation Resistance

“…[37], while other drugs in the same class, such as carvedilol and nebivolol, also have anti-cancer efficacy [38]. Propranolol has been repurposed as an anti-cancer agent due to its effects on cellular proliferation [39][40][41], migration [40], invasion [42,43], apoptosis [39,41], angiogenesis [44], treatment sensitization [41,45,46], as well as on the immune system [47][48][49][50][51][52].…”