Abstract
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.
Highlights
Among the approved drugs, Dasatinib is the first oral chemotherapeutic agent that can inhibit tyrosine protein kinase in multiple configurations
On the other hand, when the permeability and integrity of the intestine are destroyed, a large amount of bacterial products enter and damage the liver, increasing the Alanine aminotransferase AST (ALT) and AST levels in serum [13]. rough investigation of 338 patients taking Dasatinib, it was found that 60% developed liver toxicity [14]. e follow-up study found that 96 patients had elevated ALT levels and 111 people had elevated AST levels among 186 patients with chronic myeloid leukemia who took Dasatinib for 8 months [15]. erefore, it is suggested that protecting the connexin by modulating the Evidence-Based Complementary and Alternative Medicine
We previously proved that YiQiFuMai powder injection (YQFM) could reduce the expression of activated ROCK and inhibit the phosphorylation of Myosin light chain ROCK (MLC), thereby inhibiting the degradation of tight junction proteins and exerting protective effect on the brain microvascular endothelial cell barrier in vitro and in vivo [27]
Summary
Dasatinib is the first oral chemotherapeutic agent that can inhibit tyrosine protein kinase in multiple configurations. Dasatinib can inhibit the proliferation of leukemia cells in a chronic myeloid leukemia (CML) bone marrow via various kinases. It is widely used in clinics and has good therapeutic effect. Cardiovascular adverse events (CV-AEs) are considered critical complications in CML patients treated with dasatinib, suggesting probable existance of endothelial damage [3, 4]. Some studies have revealed that dasatinib induces the structure of VE-cadherin changes between endothelial cells, increasing the permeability of endothelial cells, leading to blood vessel leakage to induced gastrointestinal bleeding. E follow-up study found that 96 patients had elevated ALT levels and 111 people had elevated AST levels among 186 patients with chronic myeloid leukemia who took Dasatinib for 8 months [15]. On the other hand, when the permeability and integrity of the intestine are destroyed, a large amount of bacterial products enter and damage the liver, increasing the ALT and AST levels in serum [13]. rough investigation of 338 patients taking Dasatinib, it was found that 60% developed liver toxicity [14]. e follow-up study found that 96 patients had elevated ALT levels and 111 people had elevated AST levels among 186 patients with chronic myeloid leukemia who took Dasatinib for 8 months [15]. erefore, it is suggested that protecting the connexin by modulating the Evidence-Based Complementary and Alternative Medicine
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