Ezetimibe Anticancer Activity via the p53/Mdm2 Pathway
Background: Ezetimibe is used to treat cardiovascular disease as it blocks the sterol transporter Niemann-Pick C1-Like 1 (NPC1CL1) protein. However, recent evidence indicates that Ezetimibe inhibits several cancers indirectly by reducing circulating cholesterol or via specific signalling pathways. M...
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MDPI AG
2025-01-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/13/1/195 |
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| author | Charmy Twala Sibusiso Malindisa Chamone Munnik Selisha Sooklal Monde Ntwasa |
| author_facet | Charmy Twala Sibusiso Malindisa Chamone Munnik Selisha Sooklal Monde Ntwasa |
| author_sort | Charmy Twala |
| collection | DOAJ |
| description | Background: Ezetimibe is used to treat cardiovascular disease as it blocks the sterol transporter Niemann-Pick C1-Like 1 (NPC1CL1) protein. However, recent evidence indicates that Ezetimibe inhibits several cancers indirectly by reducing circulating cholesterol or via specific signalling pathways. Methods and Results: Our in silico studies indicate that Ezetimibe binds to the Tp53 binding domain in Mdm2, forming a more thermodynamically stable complex than nutlin3a. Furthermore, a docking study of the newly developed inhibitors—RG7388 and RG7112—was conducted. This further showed lower binding energies of −6.337 kcal/mol and −6.222 kcal/mol, respectively, when compared to the −7.919 kcal/mol exhibited by Ezetimibe. We show that Ezetimibe inhibits the growth of several cancer cell lines at concentrations that are not toxic to a normal cell line. Conclusions: Thus, Ezetimibe is probably active against cancers that overexpress Mdm2. Moreover, inhibitors of RBBP6 may be combined with Ezetimibe for effective anticancer activity. Due to poor oral bioavailability, Ezetimibe must be administered parenterally for cancer treatment. |
| format | Article |
| id | doaj-art-253f854e0417414d81ad603219ee4a20 |
| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj-art-253f854e0417414d81ad603219ee4a202025-01-24T13:24:21ZengMDPI AGBiomedicines2227-90592025-01-0113119510.3390/biomedicines13010195Ezetimibe Anticancer Activity via the p53/Mdm2 PathwayCharmy Twala0Sibusiso Malindisa1Chamone Munnik2Selisha Sooklal3Monde Ntwasa4Department of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Cnr. Pioneer and Christiaan de Wet Roads, B2-010 Calabash Building, Florida, Johannesburg 1710, South AfricaDepartment of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Cnr. Pioneer and Christiaan de Wet Roads, B2-010 Calabash Building, Florida, Johannesburg 1710, South AfricaDepartment of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Cnr. Pioneer and Christiaan de Wet Roads, B2-010 Calabash Building, Florida, Johannesburg 1710, South AfricaDepartment of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Cnr. Pioneer and Christiaan de Wet Roads, B2-010 Calabash Building, Florida, Johannesburg 1710, South AfricaDepartment of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Cnr. Pioneer and Christiaan de Wet Roads, B2-010 Calabash Building, Florida, Johannesburg 1710, South AfricaBackground: Ezetimibe is used to treat cardiovascular disease as it blocks the sterol transporter Niemann-Pick C1-Like 1 (NPC1CL1) protein. However, recent evidence indicates that Ezetimibe inhibits several cancers indirectly by reducing circulating cholesterol or via specific signalling pathways. Methods and Results: Our in silico studies indicate that Ezetimibe binds to the Tp53 binding domain in Mdm2, forming a more thermodynamically stable complex than nutlin3a. Furthermore, a docking study of the newly developed inhibitors—RG7388 and RG7112—was conducted. This further showed lower binding energies of −6.337 kcal/mol and −6.222 kcal/mol, respectively, when compared to the −7.919 kcal/mol exhibited by Ezetimibe. We show that Ezetimibe inhibits the growth of several cancer cell lines at concentrations that are not toxic to a normal cell line. Conclusions: Thus, Ezetimibe is probably active against cancers that overexpress Mdm2. Moreover, inhibitors of RBBP6 may be combined with Ezetimibe for effective anticancer activity. Due to poor oral bioavailability, Ezetimibe must be administered parenterally for cancer treatment.https://www.mdpi.com/2227-9059/13/1/195p53Mdm2drug designdrug developmentdrug repurposingEzetimibe |
| spellingShingle | Charmy Twala Sibusiso Malindisa Chamone Munnik Selisha Sooklal Monde Ntwasa Ezetimibe Anticancer Activity via the p53/Mdm2 Pathway Biomedicines p53 Mdm2 drug design drug development drug repurposing Ezetimibe |
| title | Ezetimibe Anticancer Activity via the p53/Mdm2 Pathway |
| title_full | Ezetimibe Anticancer Activity via the p53/Mdm2 Pathway |
| title_fullStr | Ezetimibe Anticancer Activity via the p53/Mdm2 Pathway |
| title_full_unstemmed | Ezetimibe Anticancer Activity via the p53/Mdm2 Pathway |
| title_short | Ezetimibe Anticancer Activity via the p53/Mdm2 Pathway |
| title_sort | ezetimibe anticancer activity via the p53 mdm2 pathway |
| topic | p53 Mdm2 drug design drug development drug repurposing Ezetimibe |
| url | https://www.mdpi.com/2227-9059/13/1/195 |
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