New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells
The synthesis of new 3-cyano-2-substituted pyridines bearing various pharmacophores and functionalities at position 2 is described. The synthesized compounds were evaluated for their in vitro anti-cancer activities on five cancer cell lines using 5-FU as reference compound. The results revealed that...
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MDPI AG
2016-02-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/21/2/230 |
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| author | Ahmed Malki Mona Mohsen Hassan Aziz Ola Rizk Omima Shaban Mohamed El-Sayed Zaki A. Sherif Hayam Ashour |
| author_facet | Ahmed Malki Mona Mohsen Hassan Aziz Ola Rizk Omima Shaban Mohamed El-Sayed Zaki A. Sherif Hayam Ashour |
| author_sort | Ahmed Malki |
| collection | DOAJ |
| description | The synthesis of new 3-cyano-2-substituted pyridines bearing various pharmacophores and functionalities at position 2 is described. The synthesized compounds were evaluated for their in vitro anti-cancer activities on five cancer cell lines using 5-FU as reference compound. The results revealed that the benzohydrazide derivative 9a induced growth inhibition in human breast cancer cell line MCF-7 with an IC50 value of 2 μM and it showed lower cytotoxicity on MCF-12a normal breast epithelial cells. Additionally, 9a induced apoptotic morphological changes and induced apoptosis in MCF-7 in a dose and time-dependent manner according to an enzyme linked immunosorbent apoptosis assay which is further confirmed by a TUNEL assay. Flow cytometric analysis indicated that 9a arrested MCF-7 cells in the G1 phase, which was further confirmed by increased expression of p21 and p27 and reduced expression of CDK2 and CDK4. Western blot data revealed significant upregulation of the expression of p53, Bax, caspase-3 and down-regulation of Bcl-2, Mdm-2 and Akt. Additionally, 9a increased the release of cytochrome c from mitochondria to cytoplasm which provokes the mitochondrial apoptotic pathway while it showed no significant change on the expression of the death receptor proteins procaspase-8, caspase-8 and FAS. Furthermore, 9a reduced the expression of phospho AKT and β-catenin in dose dependent manner while inhibiting the expression of migration-related genes such as matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF). Our findings suggest that compound 9a could be considered as a lead structure for further development of more potent apoptosis inducing agents with anti-metastatic activities. |
| first_indexed | 2024-12-13T01:53:30Z |
| format | Article |
| id | doaj.art-98305f5b1648480bb6279824a8553e1b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-13T01:53:30Z |
| publishDate | 2016-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-98305f5b1648480bb6279824a8553e1b2022-12-22T00:03:28ZengMDPI AGMolecules1420-30492016-02-0121223010.3390/molecules21020230molecules21020230New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer CellsAhmed Malki0Mona Mohsen1Hassan Aziz2Ola Rizk3Omima Shaban4Mohamed El-Sayed5Zaki A. Sherif6Hayam Ashour7Biomedical Science Program, Department of Health Sciences, College of Art and Sciences, Qatar University, Doha 2713, QatarBiomedical Science Program, Department of Health Sciences, College of Art and Sciences, Qatar University, Doha 2713, QatarBiomedical Science Program, Department of Health Sciences, College of Art and Sciences, Qatar University, Doha 2713, QatarDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, EgyptBiochemistry Department, Faculty of Science, Alexandria University, Alexandria 21521, EgyptDepartment of Biochemistry and Molecular Biology, Howard University, College of Medicine, Washington, DC 20059, USADepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, EgyptThe synthesis of new 3-cyano-2-substituted pyridines bearing various pharmacophores and functionalities at position 2 is described. The synthesized compounds were evaluated for their in vitro anti-cancer activities on five cancer cell lines using 5-FU as reference compound. The results revealed that the benzohydrazide derivative 9a induced growth inhibition in human breast cancer cell line MCF-7 with an IC50 value of 2 μM and it showed lower cytotoxicity on MCF-12a normal breast epithelial cells. Additionally, 9a induced apoptotic morphological changes and induced apoptosis in MCF-7 in a dose and time-dependent manner according to an enzyme linked immunosorbent apoptosis assay which is further confirmed by a TUNEL assay. Flow cytometric analysis indicated that 9a arrested MCF-7 cells in the G1 phase, which was further confirmed by increased expression of p21 and p27 and reduced expression of CDK2 and CDK4. Western blot data revealed significant upregulation of the expression of p53, Bax, caspase-3 and down-regulation of Bcl-2, Mdm-2 and Akt. Additionally, 9a increased the release of cytochrome c from mitochondria to cytoplasm which provokes the mitochondrial apoptotic pathway while it showed no significant change on the expression of the death receptor proteins procaspase-8, caspase-8 and FAS. Furthermore, 9a reduced the expression of phospho AKT and β-catenin in dose dependent manner while inhibiting the expression of migration-related genes such as matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF). Our findings suggest that compound 9a could be considered as a lead structure for further development of more potent apoptosis inducing agents with anti-metastatic activities.http://www.mdpi.com/1420-3049/21/2/2303-cyanopyridinesalkoxy substituentsMCF-7apoptosisp53VEGF |
| spellingShingle | Ahmed Malki Mona Mohsen Hassan Aziz Ola Rizk Omima Shaban Mohamed El-Sayed Zaki A. Sherif Hayam Ashour New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells Molecules 3-cyanopyridines alkoxy substituents MCF-7 apoptosis p53 VEGF |
| title | New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells |
| title_full | New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells |
| title_fullStr | New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells |
| title_full_unstemmed | New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells |
| title_short | New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells |
| title_sort | new 3 cyano 2 substituted pyridines induce apoptosis in mcf 7 breast cancer cells |
| topic | 3-cyanopyridines alkoxy substituents MCF-7 apoptosis p53 VEGF |
| url | http://www.mdpi.com/1420-3049/21/2/230 |
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