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cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability
| Title: | cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability |
| Authors: | Aoyama, Tsuyoshi Browse this author | | Kuriyama, Hiroki Browse this author | | Sato, Yuki Browse this author | | Imai, Shungo Browse this author | | Kashiwagi, Hitoshi Browse this author | | Sugawara, Mitsuru Browse this author | | Takekuma, Yoh Browse this author →KAKEN DB |
| Keywords: | dasatinib | | pleural effusion | | vascular endothelial (VE)-cadherin | | cell morphology | | permeability | | cAMP |
| Issue Date: | Aug-2021 |
| Publisher: | The Pharmaceutical Society of Japan （日本薬学会） |
| Journal Title: | Biological & pharmaceutical bulletin |
| Volume: | 44 |
| Issue: | 8 |
| Start Page: | 1101 |
| End Page: | 1110 |
| Publisher DOI: | 10.1248/bpb.b21-00270 |
| Abstract: | 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. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/82912 |
| Appears in Collections: | 北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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