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

• Published in: Clinical pharmacology and therapeutics 2020-09, Vol.108 (3), p.606-615
• Main Authors: Liao, Ping, Song, Kun, Zhu, Zhanwei, Liu, Zhaoqian, Zhang, Wei, Li, Wei, Hu, Jiali, Hu, Qian, Chen, Cuiyu, Chen, Bohua, McLeod, Howard L., Pei, Haiping, Chen, Ling, He, Yijing
• Format: Article
• Language: English
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1002/cpt.1894

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.