A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, Without Retaining Antibiotic Activity
Here, we describe the chemical synthesis and biological activity of a new Doxycycline derivative, designed specifically to more effectively target cancer stem cells (CSCs). In this analog, a myristic acid (14 carbon) moiety is covalently attached to the free amino group of 9-amino-Doxycycline. First...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.01528/full |
| _version_ | 1818138597337858048 |
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| author | Béla Ózsvári Luma G. Magalhães Joe Latimer Jussi Kangasmetsa Federica Sotgia Federica Sotgia Michael P. Lisanti Michael P. Lisanti |
| author_facet | Béla Ózsvári Luma G. Magalhães Joe Latimer Jussi Kangasmetsa Federica Sotgia Federica Sotgia Michael P. Lisanti Michael P. Lisanti |
| author_sort | Béla Ózsvári |
| collection | DOAJ |
| description | Here, we describe the chemical synthesis and biological activity of a new Doxycycline derivative, designed specifically to more effectively target cancer stem cells (CSCs). In this analog, a myristic acid (14 carbon) moiety is covalently attached to the free amino group of 9-amino-Doxycycline. First, we determined the IC50 of Doxy-Myr using the 3D-mammosphere assay, to assess its ability to inhibit the anchorage-independent growth of breast CSCs, using MCF7 cells as a model system. Our results indicate that Doxy-Myr is >5-fold more potent than Doxycycline, as it appears to be better retained in cells, within a peri-nuclear membranous compartment. Moreover, Doxy-Myr did not affect the viability of the total MCF7 cancer cell population or normal fibroblasts grown as 2D-monolayers, showing remarkable selectivity for CSCs. Using both gram-negative and gram-positive bacterial strains, we also demonstrated that Doxy-Myr did not show antibiotic activity, against Escherichia coli and Staphylococcus aureus. Interestingly, other complementary Doxycycline amide derivatives, with longer (16 carbon; palmitic acid) or shorter (12 carbon; lauric acid) fatty acid chain lengths, were both less potent than Doxy-Myr for the targeting of CSCs. Finally, using MDA-MB-231 cells, we also demonstrate that Doxy-Myr has no appreciable effect on tumor growth, but potently inhibits tumor cell metastasis in vivo, with little or no toxicity. In summary, by using 9-amino-Doxycycline as a scaffold, here we have designed new chemical entities for their further development as anti-cancer agents. These compounds selectively target CSCs, e.g., Doxy-Myr, while effectively minimizing the risk of driving antibiotic resistance. Taken together, our current studies provide proof-of-principle, that existing FDA-approved drugs can be further modified and optimized, to successfully target the anchorage-independent growth of CSCs and to prevent the process of spontaneous tumor cell metastasis. |
| first_indexed | 2024-12-11T10:14:43Z |
| format | Article |
| id | doaj.art-8c80ce471acf425ca74005bae7311c97 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-11T10:14:43Z |
| publishDate | 2020-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-8c80ce471acf425ca74005bae7311c972022-12-22T01:11:38ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-09-011010.3389/fonc.2020.01528562190A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, Without Retaining Antibiotic ActivityBéla Ózsvári0Luma G. Magalhães1Joe Latimer2Jussi Kangasmetsa3Federica Sotgia4Federica Sotgia5Michael P. Lisanti6Michael P. Lisanti7Translational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Manchester, United KingdomTranslational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Manchester, United KingdomSalford Antibiotic Research Network, School of Science, Engineering and Environment (SEE), University of Salford, Manchester, United KingdomEurofins Integrated Discovery UK Ltd., Essex, United KingdomTranslational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Manchester, United KingdomLunella Biotech, Inc., Ottawa, ON, CanadaTranslational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Manchester, United KingdomLunella Biotech, Inc., Ottawa, ON, CanadaHere, we describe the chemical synthesis and biological activity of a new Doxycycline derivative, designed specifically to more effectively target cancer stem cells (CSCs). In this analog, a myristic acid (14 carbon) moiety is covalently attached to the free amino group of 9-amino-Doxycycline. First, we determined the IC50 of Doxy-Myr using the 3D-mammosphere assay, to assess its ability to inhibit the anchorage-independent growth of breast CSCs, using MCF7 cells as a model system. Our results indicate that Doxy-Myr is >5-fold more potent than Doxycycline, as it appears to be better retained in cells, within a peri-nuclear membranous compartment. Moreover, Doxy-Myr did not affect the viability of the total MCF7 cancer cell population or normal fibroblasts grown as 2D-monolayers, showing remarkable selectivity for CSCs. Using both gram-negative and gram-positive bacterial strains, we also demonstrated that Doxy-Myr did not show antibiotic activity, against Escherichia coli and Staphylococcus aureus. Interestingly, other complementary Doxycycline amide derivatives, with longer (16 carbon; palmitic acid) or shorter (12 carbon; lauric acid) fatty acid chain lengths, were both less potent than Doxy-Myr for the targeting of CSCs. Finally, using MDA-MB-231 cells, we also demonstrate that Doxy-Myr has no appreciable effect on tumor growth, but potently inhibits tumor cell metastasis in vivo, with little or no toxicity. In summary, by using 9-amino-Doxycycline as a scaffold, here we have designed new chemical entities for their further development as anti-cancer agents. These compounds selectively target CSCs, e.g., Doxy-Myr, while effectively minimizing the risk of driving antibiotic resistance. Taken together, our current studies provide proof-of-principle, that existing FDA-approved drugs can be further modified and optimized, to successfully target the anchorage-independent growth of CSCs and to prevent the process of spontaneous tumor cell metastasis.https://www.frontiersin.org/article/10.3389/fonc.2020.01528/fullcancer stem-like cells (CSCs)Doxycyclinemyristic acidfatty acylationcancer cell metastasisprophylaxis of metastasis |
| spellingShingle | Béla Ózsvári Luma G. Magalhães Joe Latimer Jussi Kangasmetsa Federica Sotgia Federica Sotgia Michael P. Lisanti Michael P. Lisanti A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, Without Retaining Antibiotic Activity Frontiers in Oncology cancer stem-like cells (CSCs) Doxycycline myristic acid fatty acylation cancer cell metastasis prophylaxis of metastasis |
| title | A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, Without Retaining Antibiotic Activity |
| title_full | A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, Without Retaining Antibiotic Activity |
| title_fullStr | A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, Without Retaining Antibiotic Activity |
| title_full_unstemmed | A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, Without Retaining Antibiotic Activity |
| title_short | A Myristoyl Amide Derivative of Doxycycline Potently Targets Cancer Stem Cells (CSCs) and Prevents Spontaneous Metastasis, Without Retaining Antibiotic Activity |
| title_sort | myristoyl amide derivative of doxycycline potently targets cancer stem cells cscs and prevents spontaneous metastasis without retaining antibiotic activity |
| topic | cancer stem-like cells (CSCs) Doxycycline myristic acid fatty acylation cancer cell metastasis prophylaxis of metastasis |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.01528/full |
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