YQFM Alleviates Side Effects Caused by Dasatinib through the ROCK/MLC Pathway in Mice

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.

Dasatinib induces loss of vascular integrity and promotes cutaneous wound repair in mice

“…23 At a very high dose (≥50 mg/kg), dasatinib increases vascular leakage in the unchallenged small intestine and spleen of mice via activation of ROCK and subsequent myosin light chain phosphorylation inside endothelial cells, leading to downregulation of VE-cadherin and other associated junctional molecules. 7,24 In agreement with this, our pilot study demonstrated that high doses of dasatinib (25 and 50 mg/kg) induced severe intestinal bleeding in mice within 24 h but no vascular leakage was observed in the wound area (data not shown). These factors may contribute to adverse events following dasatinib treatment.…”

“…In rats, intraperitoneal administration of dasatinib (10 mg/kg) daily for 8 weeks leads to pleural effusion by producing a reactive oxygen species (ROS)‐induced increase in endothelial permeability, but not by inhibition of Lyn (SFK family) or activation of Rho‐associated protein kinase (ROCK, a serine‐threonine kinase) 23 . At a very high dose (≥50 mg/kg), dasatinib increases vascular leakage in the unchallenged small intestine and spleen of mice via activation of ROCK and subsequent myosin light chain phosphorylation inside endothelial cells, leading to downregulation of VE‐cadherin and other associated junctional molecules 7,24 . In agreement with this, our pilot study demonstrated that high doses of dasatinib (25 and 50 mg/kg) induced severe intestinal bleeding in mice within 24 h but no vascular leakage was observed in the wound area (data not shown).…”

“…21,22 In addition, high doses or long-term exposure to dasatinib might induce breakage of the vascular wall via its direct effect on endothelial cells, independent of inflammation in vivo. 7,23,24 In rats, intraperitoneal administration of dasatinib (10 mg/kg) daily for 8 weeks leads to pleural effusion by producing a reactive oxygen species (ROS)-induced increase in endothelial permeability, but not by inhibition of Lyn (SFK family) or activation of Rho-associated protein kinase (ROCK, a serine-threonine kinase). 23 At a very high dose (≥50 mg/kg), dasatinib increases vascular leakage in the unchallenged small intestine and spleen of mice via activation of ROCK and subsequent myosin light chain phosphorylation inside endothelial cells, leading to downregulation of VE-cadherin and other associated junctional molecules.…”

“…More importantly, inhibition of thrombin might affect the repair process because synthetic thrombin peptide has been shown to promote skin wound healing in animals by promoting angiogenesis 21,22 . In addition, high doses or long‐term exposure to dasatinib might induce breakage of the vascular wall via its direct effect on endothelial cells, independent of inflammation in vivo 7,23,24 . In rats, intraperitoneal administration of dasatinib (10 mg/kg) daily for 8 weeks leads to pleural effusion by producing a reactive oxygen species (ROS)‐induced increase in endothelial permeability, but not by inhibition of Lyn (SFK family) or activation of Rho‐associated protein kinase (ROCK, a serine‐threonine kinase) 23 .…”

Clinical Trials Targeting Aging

“…However, if treatment duration is prolonged periods of time, the health gaining effects must outweigh potential side-effects. For example: Dasatinib can cause gastrointestinal bleeding and liver damage ( Liu et al, 2020 ). A possible approach to avoid this may be combining medication, i.e., handling rapamycin-caused glucose dysmetabolism with metformin ( Blagosklonny, 2019 ).…”