Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel Activation
The arachidonic acid metabolism through 5-lipoxygenase (5-LO) pathways is involved in modulating both tumorigenesis and angiogenesis. Although anti-carcinogenic activities of certain 5-LO inhibitors have been reported, the role of zileuton, a well known 5-LO inhibitor, on the endothelial cell prolif...
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MDPI AG
2019-09-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/10/1182 |
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| author | Hyun-Joung Lim Jinbong Park Jae-Young Um Sang-Seob Lee Hyun-Jeong Kwak |
| author_facet | Hyun-Joung Lim Jinbong Park Jae-Young Um Sang-Seob Lee Hyun-Jeong Kwak |
| author_sort | Hyun-Joung Lim |
| collection | DOAJ |
| description | The arachidonic acid metabolism through 5-lipoxygenase (5-LO) pathways is involved in modulating both tumorigenesis and angiogenesis. Although anti-carcinogenic activities of certain 5-LO inhibitors have been reported, the role of zileuton, a well known 5-LO inhibitor, on the endothelial cell proliferation and angiogenesis has not been fully elucidated. Here, we report that zileuton has an anti-angiogenic effect, and the underlying mechanisms involved activation of the large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK) channel. Our results show that zileuton significantly prevented vascular endothelial growth factor (VEGF)-induced proliferation of human umbilical vein endothelial cells (HUVECs) in vitro, as well as in vivo. However, such anti-angiogenic effect of zileuton was abolished by iberiotoxin (IBTX), a BK channel blocker, suggesting zileuton-induced activation of BK channel was critical for the observed anti-angiogenic effect of zileuton. Furthermore, the anti-angiogenic effect of zileuton was, at least, due to the activation of pro-apoptotic signaling cascades which was also abolished by IBTX. Additionally, zileuton suppressed the expression of VCAM-1, ICAM-1, ETS related gene (Erg) and the production of nitric oxide (NO). Taken together, our results show that zileuton prevents angiogenesis by activating the BK channel dependent-apoptotic pathway, thus highlighting its therapeutic capacity in angiogenesis-related diseases, such as cancer. |
| first_indexed | 2024-03-12T11:18:56Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T11:18:56Z |
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| spelling | doaj.art-985be6fe8d994712825093e127bc6a002023-09-02T01:25:01ZengMDPI AGCells2073-44092019-09-01810118210.3390/cells8101182cells8101182Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel ActivationHyun-Joung Lim0Jinbong Park1Jae-Young Um2Sang-Seob Lee3Hyun-Jeong Kwak4Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyung2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28159, KoreaDepartment of Pharmacology, College of Korean Medicine, Kyung Hee University, Dongdaemun-Gu, Seoul 02447, KoreaDepartment of Pharmacology, College of Korean Medicine, Kyung Hee University, Dongdaemun-Gu, Seoul 02447, KoreaMajor of Life Science, Division of Bioconvergence, College of Convergence and Integrated Science, Kyonggi University, 154-42 Gwanggosan-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do 16227, KoreaMajor of Life Science, Division of Bioconvergence, College of Convergence and Integrated Science, Kyonggi University, 154-42 Gwanggosan-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do 16227, KoreaThe arachidonic acid metabolism through 5-lipoxygenase (5-LO) pathways is involved in modulating both tumorigenesis and angiogenesis. Although anti-carcinogenic activities of certain 5-LO inhibitors have been reported, the role of zileuton, a well known 5-LO inhibitor, on the endothelial cell proliferation and angiogenesis has not been fully elucidated. Here, we report that zileuton has an anti-angiogenic effect, and the underlying mechanisms involved activation of the large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK) channel. Our results show that zileuton significantly prevented vascular endothelial growth factor (VEGF)-induced proliferation of human umbilical vein endothelial cells (HUVECs) in vitro, as well as in vivo. However, such anti-angiogenic effect of zileuton was abolished by iberiotoxin (IBTX), a BK channel blocker, suggesting zileuton-induced activation of BK channel was critical for the observed anti-angiogenic effect of zileuton. Furthermore, the anti-angiogenic effect of zileuton was, at least, due to the activation of pro-apoptotic signaling cascades which was also abolished by IBTX. Additionally, zileuton suppressed the expression of VCAM-1, ICAM-1, ETS related gene (Erg) and the production of nitric oxide (NO). Taken together, our results show that zileuton prevents angiogenesis by activating the BK channel dependent-apoptotic pathway, thus highlighting its therapeutic capacity in angiogenesis-related diseases, such as cancer.https://www.mdpi.com/2073-4409/8/10/11825-lipoxygenase inhibitorzileutonbk channelleukotriene b4angiogenesiserg |
| spellingShingle | Hyun-Joung Lim Jinbong Park Jae-Young Um Sang-Seob Lee Hyun-Jeong Kwak Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel Activation Cells 5-lipoxygenase inhibitor zileuton bk channel leukotriene b4 angiogenesis erg |
| title | Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel Activation |
| title_full | Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel Activation |
| title_fullStr | Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel Activation |
| title_full_unstemmed | Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel Activation |
| title_short | Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel Activation |
| title_sort | zileuton a 5 lipoxygenase inhibitor exerts anti angiogenic effect by inducing apoptosis of huvec via bk channel activation |
| topic | 5-lipoxygenase inhibitor zileuton bk channel leukotriene b4 angiogenesis erg |
| url | https://www.mdpi.com/2073-4409/8/10/1182 |
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