Koh Masahiro, Takahashi Tsuyoshi, Kurokawa Yukinori, Kobayashi Teruyuki, Saito Takuro, Ishida Tomo, Serada Satoshi, Fujimoto Minoru, Naka Tetsuji, Wada Noriko, Yamashita Kotaro, Tanaka Koji, Miyazaki Yasuhiro, Makino Tomoki, Nakajima Kiyokazu, Yamasaki Makoto, Eguchi Hidetoshi, Doki Yuichiro
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Center for Intractable Disease, Kochi University, Nankoku, Japan.
Gastric Cancer. 2021 Sep;24(5):1037-1049. doi: 10.1007/s10120-021-01184-7. Epub 2021 Mar 29.
Despite improvements in gastric cancer treatment, the mortality associated with advanced gastric cancer is still high. The activation of β-adrenergic receptors by stress has been shown to accelerate the progression of several cancers. Accordingly, increasing evidence suggests that the blockade of β-adrenergic signaling can inhibit tumor growth. However, the effect of β-blockers, which target several signaling pathways, on gastric cancer remains to be elucidated. This study aimed to investigate the anti-tumor effects of propranolol, a non-selective β-blocker, on gastric cancer.
We explored the effect of propranolol on the MKN45 and NUGC3 gastric cancer cell lines. Its efficacy and the mechanism by which it exerts anti-tumor effects were examined using several assays (e.g., cell proliferation, cell cycle, apoptosis, and wound healing) and a xenograft mouse model.
We found that propranolol inhibited tumor growth and induced G1-phase cell cycle arrest and apoptosis in both cell lines. Propranolol also decreased the expression of phosphorylated CREB-ATF and MEK-ERK pathways; suppressed the expression of matrix metalloproteinase-2, 9 and vascular endothelial growth factor; and inhibited gastric cancer cell migration. In the xenograft mouse model, propranolol treatment significantly inhibited tumor growth, and immunohistochemistry revealed that propranolol led to the suppression of proliferation and induction of apoptosis.
Propranolol inhibits the proliferation of gastric cancer cells by inducing G1-phase cell cycle arrest and apoptosis. These findings indicate that propranolol might have an opportunity as a new drug for gastric cancer.
尽管胃癌治疗有所改善，但晚期胃癌相关的死亡率仍然很高。应激激活β-肾上腺素能受体已被证明会加速几种癌症的进展。因此，越来越多的证据表明，阻断β-肾上腺素能信号传导可以抑制肿瘤生长。然而，针对多种信号通路的β受体阻滞剂对胃癌的影响仍有待阐明。本研究旨在探讨非选择性β受体阻滞剂普萘洛尔对胃癌的抗肿瘤作用。
我们研究了普萘洛尔对MKN45和NUGC3胃癌细胞系的影响。使用多种检测方法（如细胞增殖、细胞周期、凋亡和伤口愈合）和异种移植小鼠模型检测其疗效及发挥抗肿瘤作用的机制。
我们发现普萘洛尔在两种细胞系中均抑制肿瘤生长，并诱导G1期细胞周期停滞和凋亡。普萘洛尔还降低了磷酸化CREB-ATF和MEK-ERK信号通路的表达；抑制了基质金属蛋白酶-2、9和血管内皮生长因子的表达；并抑制了胃癌细胞迁移。在异种移植小鼠模型中，普萘洛尔治疗显著抑制肿瘤生长，免疫组化显示普萘洛尔导致增殖抑制和凋亡诱导。
普萘洛尔通过诱导G1期细胞周期停滞和凋亡来抑制胃癌细胞的增殖。这些发现表明普萘洛尔可能有机会成为一种治疗胃癌的新药。
