title: New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells.
abstract: 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.
authors.affiliation: Biomedical Science Program, Department of Health Sciences, College of Art and Sciences, Qatar University, Doha 2713, Qatar. ahmed.malki@qu.edu.qa.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Malki
authors.affiliation: Biomedical Science Program, Department of Health Sciences, College of Art and Sciences, Qatar University, Doha 2713, Qatar. mmohsen@qf.org.qa.
authors.forename: Mona
authors.initials: M
authors.lastname: Mohsen
authors.affiliation: Biomedical Science Program, Department of Health Sciences, College of Art and Sciences, Qatar University, Doha 2713, Qatar. hassan.aziz@qu.edu.qa.
authors.forename: Hassan
authors.initials: H
authors.lastname: Aziz
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. olarizk@yahoo.com.|Department of Analytical and Pharmaceutical Chemistry, Faculty of Pharmacy &amp; Drug Manufacturing, Pharos University, Alexandria, 21311, Egypt. olarizk@yahoo.com.
authors.forename: Ola
authors.initials: O
authors.lastname: Rizk
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. omimagaber@yahoo.com.|Department of Analytical and Pharmaceutical Chemistry, Faculty of Pharmacy &amp; Drug Manufacturing, Pharos University, Alexandria, 21311, Egypt. omimagaber@yahoo.com.
authors.forename: Omima
authors.initials: O
authors.lastname: Shaban
authors.affiliation: Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21521, Egypt. mmaelsayed@yahoo.com.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Sayed
authors.affiliation: Department of Biochemistry and Molecular Biology, Howard University, College of Medicine, Washington, DC 20059, USA. zakisherif@Howard.edu.
authors.forename: Zaki A
authors.initials: ZA
authors.lastname: Sherif
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. hayamashour@ymail.com.
authors.forename: Hayam
authors.initials: H
authors.lastname: Ashour
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines
keywords: 3-cyanopyridines; MCF-7; VEGF; alkoxy substituents; apoptosis; p53