Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathway
Abstract Drug resistance is a crucial obstacle to achieve satisfactory chemotherapeutic effects. Numerous studies have shown that the PI3K/Akt signaling pathway plays a significant role in various processes of cellular events and tumor progression, while few studies have focused on the PI3K/Akt sign...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Universidade de São Paulo
2022-09-01
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| Series: | Brazilian Journal of Pharmaceutical Sciences |
| Subjects: | |
| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502022000100700&tlng=en |
| _version_ | 1811266380165545984 |
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| author | Rong Zhang Limin Huang Di Pan Wen Zhang |
| author_facet | Rong Zhang Limin Huang Di Pan Wen Zhang |
| author_sort | Rong Zhang |
| collection | DOAJ |
| description | Abstract Drug resistance is a crucial obstacle to achieve satisfactory chemotherapeutic effects. Numerous studies have shown that the PI3K/Akt signaling pathway plays a significant role in various processes of cellular events and tumor progression, while few studies have focused on the PI3K/Akt signaling pathway in drug resistance of endothelial cells. The present study aims to explore the relationship of PI3K/Akt signaling and cellular resistance to anticancer drugs in human microvessel endothelial cells (HMEC-1). We established stable sunitinib-resiatant human microvessel endothelial cells (HMEC-su) after long-term exposure to sunitinib (a small-molecule tyrosine kinase receptor inhibitor) for 12 months. HMEC-su showed significant alternations of cell morphology and exhibited a 2.32-fold higher IC50 of sunitinib than parental HMEC-1 cells. Expression of P-glycoprotein (P-gp) and breast cancer-resistance protein (ABCG2) which mediates drug efflux, increased significantly in HMEC-su lines compared with HMEC-1 cells by western blots assay. Our study further demonstrates that LY294002 (blocking the PI3K/Akt pathway) enhances the sensibility of HMEC-su to suntinib and inhibits the gene transcription and protein expression of P-gp, ABCG2 in HMEC-su cells. In conclusion, these results indicate that LY294002 could reverse P-gp and ABCG2 mediated-drug resistance to sunitinib in HMEC-su cells by inhibiting PI3K/Akt signaling. |
| first_indexed | 2024-04-12T20:42:11Z |
| format | Article |
| id | doaj.art-fe3b3d92e73f486ea566ab9308260298 |
| institution | Directory Open Access Journal |
| issn | 2175-9790 |
| language | English |
| last_indexed | 2024-04-12T20:42:11Z |
| publishDate | 2022-09-01 |
| publisher | Universidade de São Paulo |
| record_format | Article |
| series | Brazilian Journal of Pharmaceutical Sciences |
| spelling | doaj.art-fe3b3d92e73f486ea566ab93082602982022-12-22T03:17:23ZengUniversidade de São PauloBrazilian Journal of Pharmaceutical Sciences2175-97902022-09-015810.1590/s2175-97902022e191102Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathwayRong ZhangLimin Huanghttps://orcid.org/0000-0003-3053-0160Di PanWen ZhangAbstract Drug resistance is a crucial obstacle to achieve satisfactory chemotherapeutic effects. Numerous studies have shown that the PI3K/Akt signaling pathway plays a significant role in various processes of cellular events and tumor progression, while few studies have focused on the PI3K/Akt signaling pathway in drug resistance of endothelial cells. The present study aims to explore the relationship of PI3K/Akt signaling and cellular resistance to anticancer drugs in human microvessel endothelial cells (HMEC-1). We established stable sunitinib-resiatant human microvessel endothelial cells (HMEC-su) after long-term exposure to sunitinib (a small-molecule tyrosine kinase receptor inhibitor) for 12 months. HMEC-su showed significant alternations of cell morphology and exhibited a 2.32-fold higher IC50 of sunitinib than parental HMEC-1 cells. Expression of P-glycoprotein (P-gp) and breast cancer-resistance protein (ABCG2) which mediates drug efflux, increased significantly in HMEC-su lines compared with HMEC-1 cells by western blots assay. Our study further demonstrates that LY294002 (blocking the PI3K/Akt pathway) enhances the sensibility of HMEC-su to suntinib and inhibits the gene transcription and protein expression of P-gp, ABCG2 in HMEC-su cells. In conclusion, these results indicate that LY294002 could reverse P-gp and ABCG2 mediated-drug resistance to sunitinib in HMEC-su cells by inhibiting PI3K/Akt signaling.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502022000100700&tlng=enDrug resistanceEndothelial cellsP-glycoproteinSunitinibPI3K/Akt pathway |
| spellingShingle | Rong Zhang Limin Huang Di Pan Wen Zhang Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathway Brazilian Journal of Pharmaceutical Sciences Drug resistance Endothelial cells P-glycoprotein Sunitinib PI3K/Akt pathway |
| title | Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathway |
| title_full | Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathway |
| title_fullStr | Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathway |
| title_full_unstemmed | Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathway |
| title_short | Sunitinib induced resistance of endothelial cells by up-regulating P-glycoprotein and PI3K/Akt pathway |
| title_sort | sunitinib induced resistance of endothelial cells by up regulating p glycoprotein and pi3k akt pathway |
| topic | Drug resistance Endothelial cells P-glycoprotein Sunitinib PI3K/Akt pathway |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502022000100700&tlng=en |
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