title: Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling.
abstract: In this study, novel thiosemicarbazides and 1,3,4-oxadiazoles were synthesized and evaluated for their anticancer effects on human MCF-7 breast cancer cell lines. Among the synthesized derivatives studied, compound 2-(3-(4-chlorophenyl)-3-hydroxybutanoyl)-N-phenylhydrazinecarbothioamide 4c showed the highest cytotoxicity against MCF-7 breast cancer cells as it reduced cell viability to approximately 15% compared to approximately 25% in normal breast epithelial cells. Therefore, we focused on 4c for further investigations. Our data showed that 4c induced apoptosis in MCF-7 cells which was further confirmed by TUNEL assay. Western blotting analysis showed that compound 4c up-regulated the pro-survival proteins Bax, Bad and ERK1/2, while it down-regulated anti-apoptotic proteins Bcl-2, Akt and STAT-3. Additionally, 4c induced phosphorylation of SAPK/JNK in MCF-7 cells. Pretreatment of MCF-7 cells with 10 µM of JNK inhibitor significantly reduced 4c-induced apoptosis. Molecular docking results suggested that compound 4c showed a binding pattern close to the pattern observed in the structure of the lead fragment bound to JNK1. Collectively, the data of current study suggested that the thiosemicarbazide 4c might trigger apoptosis in human MCF-7 cells by targeting JNK signaling.
authors.affiliation: a Department of Health Sciences , Biomedical Sciences Program, College of Arts and Sciences, Qatar University , Doha , Qatar .
authors.forename: Ahmed
authors.initials: A
authors.lastname: Malki
authors.forename: Rasha Y
authors.initials: RY
authors.lastname: Elbayaa
authors.forename: Hayam M A
authors.initials: HM
authors.lastname: Ashour
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Loffredo
authors.forename: Amal M
authors.initials: AM
authors.lastname: Youssef
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012663:Semicarbazides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D012663:Semicarbazides; C005151:thiosemicarbazide
keywords: 1,3,4-Oxadiazoles; JNK signaling; MCF-7 breast cancer cells; apoptosis; docking; flow cytometry; thiosemicarbazides