New 3-cyano-2-substituted pyridines induce apoptosis in MCF 7 breast cancer cells

Ahmed Malki, Mona Mohsen, Hassan Abdel-Aziz, Ola Rizk, Omaima Shaaban, Mohamed El-Sayed, Zaki A. Sherif, Hayam Ashour

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article number230
JournalMolecules
Volume21
Issue number2
DOIs
StatePublished - Feb 1 2016

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Pyridines
apoptosis
breast
pyridines
Caspase 8
cancer
Cells
Apoptosis
Breast Neoplasms
Assays
Bearings (structural)
Cell Line
Catenins
Death Domain Receptors
Immunosorbents
Mitochondria
Matrix Metalloproteinase 9
MCF-7 Cells
In Situ Nick-End Labeling
G1 Phase

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Malki, A., Mohsen, M., Abdel-Aziz, H., Rizk, O., Shaaban, O., El-Sayed, M., ... Ashour, H. (2016). New 3-cyano-2-substituted pyridines induce apoptosis in MCF 7 breast cancer cells. Molecules, 21(2), [230]. https://doi.org/10.3390/molecules21020230

New 3-cyano-2-substituted pyridines induce apoptosis in MCF 7 breast cancer cells. / Malki, Ahmed; Mohsen, Mona; Abdel-Aziz, Hassan; Rizk, Ola; Shaaban, Omaima; El-Sayed, Mohamed; Sherif, Zaki A.; Ashour, Hayam.

In: Molecules, Vol. 21, No. 2, 230, 01.02.2016.

Research output: Contribution to journalArticle

Malki, A, Mohsen, M, Abdel-Aziz, H, Rizk, O, Shaaban, O, El-Sayed, M, Sherif, ZA & Ashour, H 2016, 'New 3-cyano-2-substituted pyridines induce apoptosis in MCF 7 breast cancer cells', Molecules, vol. 21, no. 2, 230. https://doi.org/10.3390/molecules21020230
Malki, Ahmed ; Mohsen, Mona ; Abdel-Aziz, Hassan ; Rizk, Ola ; Shaaban, Omaima ; El-Sayed, Mohamed ; Sherif, Zaki A. ; Ashour, Hayam. / New 3-cyano-2-substituted pyridines induce apoptosis in MCF 7 breast cancer cells. In: Molecules. 2016 ; Vol. 21, No. 2.
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