cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability

Tsuyoshi Aoyama, Hiroki Kuriyama, Yuki Sato, Shungo Imai, Hitoshi Kashiwagi, Mitsuru Sugawara, Yoh Takekuma

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1101-1110
Number of pages10
JournalBiological and Pharmaceutical Bulletin
Volume44
Issue number8
DOIs
Publication statusPublished - 2021 Aug
Externally publishedYes

Keywords

  • CAMP
  • Cell morphology
  • Dasatinib
  • Permeability
  • Pleural effusion
  • Vascular endothelial (VE)-cadherin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Fingerprint

Dive into the research topics of 'cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability'. Together they form a unique fingerprint.

Cite this