Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines.

Abstract

The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER(+) and ER(-) breast cancer cell lines.

• Authors: Helen Shiphrah Vethakanraj, Thabraz Ahmed Babu, Ganesh Babu Sudarsanan, Prabhu Kumar Duraisamy, Sekar Ashok Kumar
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 464 Issue 3 Pg. 833-9 (Aug 28 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 26188095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 3-(3-(4-methoxyphenyl)acryloyl)-4-phenyl-1H-quinolin-2-one
• Antineoplastic Agents
• Ceramides
• Enzyme Inhibitors
• Quinolones
• Tamoxifen
• ASAH1 protein, human
• Acid Ceramidase

Topics

• Acid Ceramidase (antagonists & inhibitors)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Survival (drug effects)
• Ceramides (metabolism)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inhibitory Concentration 50
• MCF-7 Cells (drug effects)
• Metabolic Networks and Pathways (drug effects)
• Molecular Targeted Therapy
• Quinolones (pharmacology)
• Tamoxifen (pharmacology)