Liu Yuankai, Dai Yujie, Xu Han, Zhou Qianliu, Li Fang, Yu Boyang, Zhang Yuanyuan, Kou Junping
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China.
Evid Based Complement Alternat Med. 2020 Aug 29;2020:4646029. doi: 10.1155/2020/4646029. eCollection 2020.
Dasatinib, as a second-generation broad-spectrum tyrosine kinase inhibitor, presents an antitumor effect by inhibiting tyrosine kinases. However, dasatinib causes serious side effects, such as gastrointestinal bleeding and liver toxicity, possibly through the activation of ROCK kinase and MLC phosphorylation. At present, there is no effective prevention and treatment method. Previous research studies have shown that YQFM (YiQiFuMai powder injection) protects the blood-brain barrier by inhibiting the ROCK/MLC signaling pathway; whether YQFM can alleviate the side effects of dasatinib is unknown. In this study, dasatinib was injected (i.p. 70 mg/kg) and YQFM (i.p. 0.336 g/kg, 0.672 g/kg, 1.342 g/kg) was given in advance for 3 days to mice, to explore the effect of YQFM on side effects induced by Dasatinib. The results confirmed that YQFM significantly decreased Evans blue leakage in the small intestine and increased intestinal blood flow, increased the expression of ZO-1, Occludin, and VE-cadherin, and reduced the contents of D-lactic acid, s-VE-cadherin, Alanine aminotransferase (ALT), and Aspartate aminotransferase (AST) in serum. Finally, YQFM inhibited the expression of ROCK-1 and phosphorylation of MLC induced by Dasatinib. These findings suggested that YQFM could improve the side effects caused by Dasatinib linked with the ROCK/MLC signaling pathway, as shown in the graphical abstract.
达沙替尼作为第二代广谱酪氨酸激酶抑制剂，通过抑制酪氨酸激酶发挥抗肿瘤作用。然而，达沙替尼会引发严重的副作用，如胃肠道出血和肝毒性，可能是通过激活ROCK激酶和MLC磷酸化。目前，尚无有效的防治方法。先前的研究表明，益气复脉粉针剂（YQFM）通过抑制ROCK/MLC信号通路保护血脑屏障；YQFM是否能减轻达沙替尼的副作用尚不清楚。在本研究中，给小鼠腹腔注射达沙替尼（70 mg/kg），并提前3天腹腔注射YQFM（0.336 g/kg、0.672 g/kg、1.342 g/kg），以探究YQFM对达沙替尼诱导的副作用的影响。结果证实，YQFM显著降低了小肠中伊文思蓝渗漏并增加了肠血流量，增加了ZO-1、闭合蛋白和血管内皮钙黏蛋白的表达，并降低了血清中D-乳酸、可溶性血管内皮钙黏蛋白、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）的含量。最后，YQFM抑制了达沙替尼诱导的ROCK-1表达和MLC磷酸化。如图形摘要所示，这些发现表明YQFM可以改善由达沙替尼与ROCK/MLC信号通路相关引起的副作用。
