DataSheet_1_Clinical Use of Propranolol Reduces Biomarkers of Proliferation in Gastric Cancer.pdf

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.

胃癌是全球死亡率最高的恶性肿瘤之一，但其临床治疗手段仍较为有限。本研究在既往研究基础之上，针对普萘洛尔（propranolol）在胃癌小鼠模型及胃癌患者中的作用机制开展了实验研究。普萘洛尔可呈时间及浓度依赖性方式抑制胃癌细胞的体外增殖活性。在615小鼠MFC移植瘤模型中，同样得到了一致的实验结果：该模型小鼠每日给予10mg/kg的普萘洛尔，连续给药14天，可显著抑制肿瘤生长。相较于对照组，普萘洛尔处理组小鼠肿瘤组织中的AKT、MEK及ERK蛋白磷酸化水平均受到抑制，具体数值为（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）。针对术前每日口服60mg普萘洛尔、连续给药7天的胃癌患者的研究也显示，普萘洛尔具有抗增殖活性（Ki67增殖指数：普萘洛尔组44.8 vs 安慰剂组125.3；P=0.02）。但在胃癌患者中，普萘洛尔与安慰剂治疗组的AKT、MEK及ERK蛋白磷酸化水平并无显著统计学差异。无论是在小鼠模型还是患者体内，CD8+ T细胞（CD8+ T cell）表面分子的表达均未发生显著改变；患者体内的CD8+ T细胞亚群比例也未出现具有统计学意义的显著差异，尽管存在一定的效应趋势。本研究结果证实，普萘洛尔可在小鼠模型及胃癌患者体内抑制胃癌的生长，其潜在作用机制可能与阻断AKT及MAPK信号通路有关，但并未显著提高肿瘤浸润CD8+ T细胞的浸润频率。