Suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft-targeted alkylphospholipid edelfosine
Metastasis is the leading cause of cancer mortality. Metastatic cancer is notoriously difficult to treat, and it accounts for the majority of cancer-related deaths. The ether lipid edelfosine is the prototype of a family of synthetic antitumor compounds collectively known as alkylphospholipid analog...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332224000301 |
| _version_ | 1797324321516945408 |
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| author | Verónica Alonso-Pérez Vanessa Hernández Marco A. Calzado Alba Vicente-Blázquez Consuelo Gajate Rafael Soler-Torronteras Kathleen DeCicco-Skinner Angels Sierra Faustino Mollinedo |
| author_facet | Verónica Alonso-Pérez Vanessa Hernández Marco A. Calzado Alba Vicente-Blázquez Consuelo Gajate Rafael Soler-Torronteras Kathleen DeCicco-Skinner Angels Sierra Faustino Mollinedo |
| author_sort | Verónica Alonso-Pérez |
| collection | DOAJ |
| description | Metastasis is the leading cause of cancer mortality. Metastatic cancer is notoriously difficult to treat, and it accounts for the majority of cancer-related deaths. The ether lipid edelfosine is the prototype of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs, and its antitumor activity involves lipid raft reorganization. In this study, we examined the effect of edelfosine on metastatic colonization and angiogenesis. Using non-invasive bioluminescence imaging and histological examination, we found that oral administration of edelfosine in nude mice significantly inhibited the lung and brain colonization of luciferase-expressing 435-Lung-eGFP-CMV/Luc metastatic cells, resulting in prolonged survival. In metastatic 435-Lung and MDA-MB-231 breast cancer cells, we found that edelfosine also inhibited cell adhesion to collagen-I and laminin-I substrates, cell migration in chemotaxis and wound-healing assays, as well as cancer cell invasion. In 435-Lung and other MDA-MB-435-derived sublines with different organotropism, edelfosine induced G2/M cell cycle accumulation and apoptosis in a concentration- and time-dependent manner. Edelfosine also inhibited in vitro angiogenesis in human and mouse endothelial cell tube formation assays. The antimetastatic properties were specific to cancer cells, as edelfosine had no effects on viability in non-cancerous cells. Edelfosine accumulated in membrane rafts and endoplasmic reticulum of cancer cells, and membrane raft-located CD44 was downregulated upon drug treatment. Taken together, this study highlights the potential of edelfosine as an attractive drug to prevent metastatic growth and organ colonization in cancer therapy. The raft-targeted drug edelfosine displays a potent activity against metastatic organ colonization and angiogenesis, two major hallmarks of tumor malignancy. |
| first_indexed | 2024-03-08T05:55:26Z |
| format | Article |
| id | doaj.art-2ecb67869ac54371a32f9c4d11807b5c |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-08T05:55:26Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-2ecb67869ac54371a32f9c4d11807b5c2024-02-05T04:31:17ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-02-01171116149Suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft-targeted alkylphospholipid edelfosineVerónica Alonso-Pérez0Vanessa Hernández1Marco A. Calzado2Alba Vicente-Blázquez3Consuelo Gajate4Rafael Soler-Torronteras5Kathleen DeCicco-Skinner6Angels Sierra7Faustino Mollinedo8Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, SpainBiological Clues of the Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), E-08907 L′Hospitalet de Llobregat, Barcelona, SpainInstituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), E-14004 Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, E-14004 Córdoba, Spain; Hospital Universitario Reina Sofía, E-14004 Córdoba, SpainLaboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, C/ Ramiro de Maeztu 9, E-28040 Madrid, Spain; Department of Biology, American University, Washington, DC 20016, USAInstituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, C/ Ramiro de Maeztu 9, E-28040 Madrid, SpainInstituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), E-14004 Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, E-14004 Córdoba, Spain; Hospital Universitario Reina Sofía, E-14004 Córdoba, SpainDepartment of Biology, American University, Washington, DC 20016, USABiological Clues of the Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), E-08907 L′Hospitalet de Llobregat, Barcelona, Spain; Laboratory of Experimental Oncological Neurosurgery, Neurosurgery Service, Hospital Clinic de Barcelona-FCRB, E-08036 Barcelona, Spain; Department of Medicine and Life Sciences (MELIS), Faculty of Health and Live Sciences, Universitat Pompeu Fabra, E-08036 Barcelona, SpainInstituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, C/ Ramiro de Maeztu 9, E-28040 Madrid, Spain; Corresponding author at: Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, CSIC, C/ Ramiro de Maeztu 9, E-28040 Madrid, Spain.Metastasis is the leading cause of cancer mortality. Metastatic cancer is notoriously difficult to treat, and it accounts for the majority of cancer-related deaths. The ether lipid edelfosine is the prototype of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs, and its antitumor activity involves lipid raft reorganization. In this study, we examined the effect of edelfosine on metastatic colonization and angiogenesis. Using non-invasive bioluminescence imaging and histological examination, we found that oral administration of edelfosine in nude mice significantly inhibited the lung and brain colonization of luciferase-expressing 435-Lung-eGFP-CMV/Luc metastatic cells, resulting in prolonged survival. In metastatic 435-Lung and MDA-MB-231 breast cancer cells, we found that edelfosine also inhibited cell adhesion to collagen-I and laminin-I substrates, cell migration in chemotaxis and wound-healing assays, as well as cancer cell invasion. In 435-Lung and other MDA-MB-435-derived sublines with different organotropism, edelfosine induced G2/M cell cycle accumulation and apoptosis in a concentration- and time-dependent manner. Edelfosine also inhibited in vitro angiogenesis in human and mouse endothelial cell tube formation assays. The antimetastatic properties were specific to cancer cells, as edelfosine had no effects on viability in non-cancerous cells. Edelfosine accumulated in membrane rafts and endoplasmic reticulum of cancer cells, and membrane raft-located CD44 was downregulated upon drug treatment. Taken together, this study highlights the potential of edelfosine as an attractive drug to prevent metastatic growth and organ colonization in cancer therapy. The raft-targeted drug edelfosine displays a potent activity against metastatic organ colonization and angiogenesis, two major hallmarks of tumor malignancy.http://www.sciencedirect.com/science/article/pii/S0753332224000301Metastatic organ colonizationMetastasisAngiogenesisAntitumor activityEdelfosineAlkylphospholipid analog |
| spellingShingle | Verónica Alonso-Pérez Vanessa Hernández Marco A. Calzado Alba Vicente-Blázquez Consuelo Gajate Rafael Soler-Torronteras Kathleen DeCicco-Skinner Angels Sierra Faustino Mollinedo Suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft-targeted alkylphospholipid edelfosine Biomedicine & Pharmacotherapy Metastatic organ colonization Metastasis Angiogenesis Antitumor activity Edelfosine Alkylphospholipid analog |
| title | Suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft-targeted alkylphospholipid edelfosine |
| title_full | Suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft-targeted alkylphospholipid edelfosine |
| title_fullStr | Suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft-targeted alkylphospholipid edelfosine |
| title_full_unstemmed | Suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft-targeted alkylphospholipid edelfosine |
| title_short | Suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft-targeted alkylphospholipid edelfosine |
| title_sort | suppression of metastatic organ colonization and antiangiogenic activity of the orally bioavailable lipid raft targeted alkylphospholipid edelfosine |
| topic | Metastatic organ colonization Metastasis Angiogenesis Antitumor activity Edelfosine Alkylphospholipid analog |
| url | http://www.sciencedirect.com/science/article/pii/S0753332224000301 |
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