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AuthorMalki, Ahmed
AuthorMohsen, Mona
AuthorAziz, Hassan
AuthorRizk, Ola
AuthorShaban, Omima
AuthorEl-Sayed, Mohamed
AuthorSherif, Zaki A.
AuthorAshour, Hayam
Available date2016-10-06T10:14:07Z
Publication Date2016-02-18
Publication NameMoleculesen_US
Identifierhttp://dx.doi.org/10.3390/molecules21020230
CitationMalki, A., Mohsen, M., Aziz, H., Rizk, O., Shaban, O., El-Sayed, M., A. Sherif, Z., Ashour, H.(2016),” New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells”,21(2), 230.
ISSN1420-3049
URIhttp://hdl.handle.net/10576/4832
AbstractThe 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.
Languageen
PublisherMultidisciplinary Digital Publishing Institute (MDPI)
Subject3-cyanopyridines
Subjectalkoxy substituents
SubjectMCF-7
Subjectapoptosis
Subjectp53
SubjectVEGF
TitleNew 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells
TypeArticle
Issue Number2
Volume Number21


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