2. Academic Validation
  3. Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells

Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells

  • Int J Pharm. 2019 Dec 15;572:118762. doi: 10.1016/j.ijpharm.2019.118762.
Tomoya Takenaka 1,  Shinya Nakai 1,  Miku Katayama 1,  Mami Hirano 1,  Natsumi Ueno 1,  Kosuke Noguchi 1,  Tomoka Takatani-Nakase 2,  Ikuo Fujii 3,  Susumu S Kobayashi 4,  Ikuhiko Nakase 5
Affiliations

Affiliations

  • 1 NanoSquare Research Institute, Research Center for the 21st Century, Organization for Research Promotion, Osaka Prefecture University, Sakai, Osaka 599-8570, Japan; Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8570, Japan.
  • 2 Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo 663-8179, Japan.
  • 3 Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8570, Japan.
  • 4 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. Electronic address: sukobaya@east.ncc.go.jp.
  • 5 NanoSquare Research Institute, Research Center for the 21st Century, Organization for Research Promotion, Osaka Prefecture University, Sakai, Osaka 599-8570, Japan; Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8570, Japan. Electronic address: i-nakase@21c.osakafu-u.ac.jp.
PMID: 31610280 DOI: 10.1016/j.ijpharm.2019.118762
Abstract

Extracellular vesicles (exosomes, EVs) are cell membrane particles (30-200 nm) secreted by virtually all cells. During intercellular communication in the body, secreted EVs play crucial roles by carrying functional biomolecules (e.g., MicroRNAs and Enzymes) into other cells to affect cellular function, including disease progression. We previously reported that the macropinocytosis pathway contributes greatly to the efficient cellular uptake of EVs. The activation of growth factor receptors, such as epidermal growth factor receptor (EGFR), induces macropinocytosis. In this study, we demonstrated the effects of gefitinib, a tyrosine kinase inhibitor of EGFR, on the cellular uptake of EVs. In EGFR-mutant HCC827 non-small cell lung Cancer (NSCLC) cells, which are sensitive to gefitinib, macropinocytosis was suppressed by gefitinib treatment. However, the cellular uptake of EVs was increased by gefitinib treatment, whereas that of liposomes was reduced. In accordance with the results of the cellular uptake studies, the anti-cancer activity of doxorubicin (DOX)-loaded EVs in HCC827 cells was significantly increased in the presence of gefitinib, whereas the activity of DOX-loaded liposomes was reduced. The digestion of EV proteins by trypsin did not affect uptake, suggesting that the cellular uptake of EVs might not be mediated by EV proteins. These results suggest that gefitinib can enhance cell-to-cell communication via EVs within the tumor microenvironment. In addition, EVs show potential as Drug Delivery vehicles in combination with gefitinib for the treatment of patients harboring EGFR-mutant NSCLC tumors.

Keywords

EGFR; Exosomes; Extracellular vesicles; Gefitinib; Non-small cell lung cancer.

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