cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability

• Published in: Biological & pharmaceutical bulletin 2021/08/01, Vol.44(8), pp.1101-1110
• Main Authors: Aoyama, Tsuyoshi, Kuriyama, Hiroki, Sato, Yuki, Imai, Shungo, Kashiwagi, Hitoshi, Sugawara, Mitsuru, Takekuma, Yoh
• Format: Article
• Language: English
• Subjects: Aniline Compounds - pharmacology; Antigens, CD - metabolism; Cadherins; Cadherins - metabolism; cAMP; Capillary Permeability - drug effects; Cell Culture Techniques; cell morphology; Chronic myeloid leukemia; Cyclic AMP; Cyclic AMP - metabolism; Cytology; Cytotoxicity; dasatinib; Dasatinib - adverse effects; Dasatinib - therapeutic use; Endothelial cells; Endothelial Cells - drug effects; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Enzyme inhibitors; Epithelial cells; Human Umbilical Vein Endothelial Cells; Humans; Imatinib; Imatinib Mesylate - pharmacology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Membrane permeability; Myeloid leukemia; Nitriles - pharmacology; Permeability; Pleural effusion; Pleural Effusion - chemically induced; Pleural Effusion - metabolism; Protein Kinase Inhibitors - adverse effects; Protein-tyrosine kinase; Quinolines - pharmacology; Signal Transduction; vascular endothelial (VE)-cadherin
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b21-00270

Dasatinib is a first-line pharmacotherapeutic treatment for chronic myeloid leukemia (CML). It is more effective than traditional treatments but causes adverse effects such as pleural effusion that limits its effective treatment cycle. Since pleural effusion is caused by vascular hyperpermeability and causes discontinuation of treatment with dasatinib, it is important to explore the mechanism of pleural effusion caused by dasatinib and how to prevent it. In this study, we investigated how dasatinib increase vascular permeability, and how it can be prevented. Cytotoxicity was observed in vascular endothelial cells or epithelial cells were exposed to high concentrations of dasatinib. Thus, it was observed in vascular endothelial cells such as human umbilical vascular endothelial cell (HUVEC). Vascular endothelial (VE)-cadherin is one of the important factors that control vascular permeability. When VE-cadherin expression decreases, vascular permeability increases, but it did not change with tyrosine kinase inhibitor exposure. Monolayer permeability significantly increased only with high concentration of dasatinib, but this increase was prevented by cAMP activation. Furthermore, dasatinib affects the cell morphology of HUVEC, with increased inter celluar space compared to control and bosutinib, which were also attenuated by cAMP activation. Dasatinib significantly affected permeability control of vascular endothelial cells compared to bosutinib and imatinib. These results indicated that the cAMP signaling pathway may be involved in the pleural effusion caused by dasatinib in CML patients.