Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner
BTK inhibitor (BTKi) Ibrutinib carries an increased bleeding risk compared to more selective BTKis Acalabrutinib and Zanubrutinib, however, its impact on vascular endothelium remains unknown. In this study, we found that Ibrutinib induced stronger cytotoxic effect on endothelial cells than Zanubruti...
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MDPI AG
2022-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/9/1876 |
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| author | Jia Liu Zhuojun Liu Jing Zhang Xiaofang Chen Junge Chen Linlin Sui Jian Yu |
| author_facet | Jia Liu Zhuojun Liu Jing Zhang Xiaofang Chen Junge Chen Linlin Sui Jian Yu |
| author_sort | Jia Liu |
| collection | DOAJ |
| description | BTK inhibitor (BTKi) Ibrutinib carries an increased bleeding risk compared to more selective BTKis Acalabrutinib and Zanubrutinib, however, its impact on vascular endothelium remains unknown. In this study, we found that Ibrutinib induced stronger cytotoxic effect on endothelial cells than Zanubrutinib, however, Acalabrutinib cytotoxicity was extremely weak. RNA-seq, followed by KEGG analysis and quantitative RT-PCR validation, was conducted to identify the differential apoptotic target genes of BTKis, leading to their distinct cytotoxic effects on endothelial cells, which showed that Ibrutinib and Zanubrutinib dramatically modulated the expression of critical apoptotic genes, <i>GADD45B</i>, <i>FOS</i>, and <i>BCL2A1</i>, among which <i>FOS</i> and <i>GADD45B</i> were upregulated more significantly by Ibrutinib than Zanubrutinib, however, Acalabrutinib downregulated <i>BCL2A1</i> moderately and was not able to modulate the expression of <i>FOS</i> and <i>GADD45B</i>. Next, we performed in vitro angiogenesis assays and found that Ibrutinib was more able to induce endothelial dysfunction than Zanubrutinib via stimulating more BMP4 expression, however, Acalabrutinib had no such effect. Especially, the capacity of Ibrutinib to induce endothelial dysfunction can be antagonized by targeting BMP4. Accordingly, Ibrutinib, as an angiogenesis inhibitor, inhibited ovarian and breast cancer progression in vivo. Collectively, our findings addressed a novel molecular basis underlying Ibrutinib-induced endothelial cell dysfunction and suggested the potential application of Ibrutinib to treat angiogenesis-dependent cancers. |
| first_indexed | 2024-03-09T22:50:23Z |
| format | Article |
| id | doaj.art-7046680022b04427a3e8a2f99edc11d4 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T22:50:23Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-7046680022b04427a3e8a2f99edc11d42023-11-23T18:22:13ZengMDPI AGPharmaceutics1999-49232022-09-01149187610.3390/pharmaceutics14091876Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent MannerJia Liu0Zhuojun Liu1Jing Zhang2Xiaofang Chen3Junge Chen4Linlin Sui5Jian Yu6School of Engineering Medicine, Beihang University, Beijing 100083, ChinaSchool of Engineering Medicine, Beihang University, Beijing 100083, ChinaSchool of Engineering Medicine, Beihang University, Beijing 100083, ChinaSchool of Engineering Medicine, Beihang University, Beijing 100083, ChinaSchool of Engineering Medicine, Beihang University, Beijing 100083, ChinaCore Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116000, ChinaSchool of Engineering Medicine, Beihang University, Beijing 100083, ChinaBTK inhibitor (BTKi) Ibrutinib carries an increased bleeding risk compared to more selective BTKis Acalabrutinib and Zanubrutinib, however, its impact on vascular endothelium remains unknown. In this study, we found that Ibrutinib induced stronger cytotoxic effect on endothelial cells than Zanubrutinib, however, Acalabrutinib cytotoxicity was extremely weak. RNA-seq, followed by KEGG analysis and quantitative RT-PCR validation, was conducted to identify the differential apoptotic target genes of BTKis, leading to their distinct cytotoxic effects on endothelial cells, which showed that Ibrutinib and Zanubrutinib dramatically modulated the expression of critical apoptotic genes, <i>GADD45B</i>, <i>FOS</i>, and <i>BCL2A1</i>, among which <i>FOS</i> and <i>GADD45B</i> were upregulated more significantly by Ibrutinib than Zanubrutinib, however, Acalabrutinib downregulated <i>BCL2A1</i> moderately and was not able to modulate the expression of <i>FOS</i> and <i>GADD45B</i>. Next, we performed in vitro angiogenesis assays and found that Ibrutinib was more able to induce endothelial dysfunction than Zanubrutinib via stimulating more BMP4 expression, however, Acalabrutinib had no such effect. Especially, the capacity of Ibrutinib to induce endothelial dysfunction can be antagonized by targeting BMP4. Accordingly, Ibrutinib, as an angiogenesis inhibitor, inhibited ovarian and breast cancer progression in vivo. Collectively, our findings addressed a novel molecular basis underlying Ibrutinib-induced endothelial cell dysfunction and suggested the potential application of Ibrutinib to treat angiogenesis-dependent cancers.https://www.mdpi.com/1999-4923/14/9/1876IbrutinibAcalabrutinibZanubrutinibvascular endothelial dysfunctionangiogenesis inhibitor |
| spellingShingle | Jia Liu Zhuojun Liu Jing Zhang Xiaofang Chen Junge Chen Linlin Sui Jian Yu Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner Pharmaceutics Ibrutinib Acalabrutinib Zanubrutinib vascular endothelial dysfunction angiogenesis inhibitor |
| title | Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner |
| title_full | Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner |
| title_fullStr | Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner |
| title_full_unstemmed | Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner |
| title_short | Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner |
| title_sort | ibrutinib inhibits angiogenesis and tumorigenesis in a btk independent manner |
| topic | Ibrutinib Acalabrutinib Zanubrutinib vascular endothelial dysfunction angiogenesis inhibitor |
| url | https://www.mdpi.com/1999-4923/14/9/1876 |
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