title: 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.affiliation: Centre for Biotechnology, Anna University, Chennai, India.
authors.forename: Helen Shiphrah
authors.initials: HS
authors.lastname: Vethakanraj
authors.affiliation: Centre for Biotechnology, Anna University, Chennai, India.
authors.forename: Thabraz Ahmed
authors.initials: TA
authors.lastname: Babu
authors.affiliation: Centre for Biotechnology, Anna University, Chennai, India.
authors.forename: Ganesh Babu
authors.initials: GB
authors.lastname: Sudarsanan
authors.affiliation: Centre for Biotechnology, Anna University, Chennai, India.
authors.forename: Prabhu Kumar
authors.initials: PK
authors.lastname: Duraisamy
authors.affiliation: Centre for Biotechnology, Anna University, Chennai, India. Electronic address: sekarashok@gmail.com.
authors.forename: Sekar
authors.initials: S
authors.lastname: Ashok Kumar
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells / Q000187:drug effects; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D058990:Molecular Targeted Therapy; D015363:Quinolones / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: C000602531:3-(3-(4-methoxyphenyl)acryloyl)-4-phenyl-1H-quinolin-2-one; D000970:Antineoplastic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; D015363:Quinolones; D013629:Tamoxifen; C526693:ASAH1 protein, human; D055573:Acid Ceramidase
keywords: Acid ceramidase; Apoptosis; Breast cancer cell lines; Ceranib 2