Ruscogenin Alleviates Intestinal Bleeding and Blood Flow Induced by Dasatinib through ROCK/MLC Pathway

Abstract

BackgroundAs 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.MethodsC57BL/6 mice and HUVECs were used to evaluate the side effects caused by dasatinib, RUS was administered in advance to prevent, protein expression and phosphorylation were measured by western blot, and monitored the intestinal bleeding with Laser Doppler Blood Flow Monitor. ResultsWe found that Ruscogenin (RUS) can improve Side effects caused by Dasatinib. Through the Laser Doppler Blood Flow Monitor, it was found that after Dasatinib was administered, blood flow in mice are 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. ConclusionsThis study provides a new direction for improving the side effects caused by clinical drugs and confirm that Ruscogenin could improve the side effect from Dasatinib by ROCK/MLC pathway.