Clinical Use of Propranolol Reduces Biomarkers of Proliferation in Gastric Cancer

Qian Hu; Ping Liao; Wei Li; Jiali Hu; Cuiyu Chen; Yu Zhang; Yang Wang; Ling Chen; Kun Song; Jie Liu; Wei Zhang; Qing Li; Howard L McLeod; Yijing He

doi:10.3389/fonc.2021.628613

Clinical Use of Propranolol Reduces Biomarkers of Proliferation in Gastric Cancer

Front Oncol. 2021 Apr 26:11:628613. doi: 10.3389/fonc.2021.628613. eCollection 2021.

Authors

Qian Hu^{1

2

3}, Ping Liao^{1

2

3

4}, Wei Li^{1

2

3}, Jiali Hu^{1

2

3}, Cuiyu Chen^{1

2

3}, Yu Zhang^{1

2

3}, Yang Wang^{1

2

3}, Ling Chen⁵, Kun Song⁵, Jie Liu^{1

2

3}, Wei Zhang^{1

2

3}, Qing Li^{1

2

3}, Howard L McLeod^{1

2

3

6}, Yijing He^{1

2

3}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
² Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, China.
⁵ Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China.
⁶ USF Taneja College of Pharmacy, Tampa, FL, United States.

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.

Keywords: AKT/MAPK; CD8+ T cell; anti-proliferation; gastric; immunity; propranolol.