Ruscogenin alleviates intestinal bleeding and blood flow induced by Dasatinib through ROCK/MLC pathway

Abstract As a second-generation broad-spectrum tyrosine kinase inhibitor, Dasatinib has the antitumor effect of inhibiting tyrosine kinases such as BCR-ABL and SRC. It is mainly used to treat chronic and acute patients with chronic myelogenous leukemia. However, Dasatinib has many side effects, including gastrointestinal bleeding, respiratory infections, and renal failure, and effective means to improve the side effects of drugs are lacking. The occurrence of gastrointestinal bleeding is mainly due to the destruction of the vascular endothelial barrier by Dasatinib. For the first time, we administered a large dose of oral administration and monitored the intestinal bleeding with a laser Doppler flowmeter. We found that Ruscogenin (RUS) can improve dasatin Side effects caused by tinib. Through Doppler flowmeter detection, it was found that after Dasatinib was administered, blood flow in mice decreased, and intestinal Evans blue leakage increased. Western blot results showed that connexin (ZO-1, VE-cadherin, Occludin) is destroyed, the activation of ROCK increases, and the phosphorylation of MLC increases. Ruscogenin can reverse the above phenomenon and improve the side effects of gastrointestinal bleeding caused by Dasatinib. In vitro, giving Ruscogenin in advance can protect the endothelial barrier damage caused by Dasatinib, reduce the remodeling of F-actin, and restore the expression of connexin (ZO-1, VE-cadherin), inhibit the activation of ROCK, and reduce Phosphorylation of MLC. This study provides a new direction for improving the side effects caused by clinical drugs.