title: Novel ferrocenyl pyrazoles inhibit breast cancer cell viability via induction of apoptosis and inhibition of PI3K/Akt and ERK1/2 signaling.
abstract: Despite the advances in early detection and targeted therapies, chemotherapy is still of vital importance in breast cancer treatment. However, development of drug resistance and serious side effects limits their usage. Thus, there is an urgent need for safer and more effective agents against breast cancer. We have previously described the synthesis of a number of pyrazole derivatives, and in the current study, we have investigated the effects of two different ferrocenyl pyrazole (FP) derivates, 5-ferrocenyl-1-phenyl-1H-pyrazole (FP-Ph) and 5-ferrocenyl-1H-pyrazole (FP-H), on breast cancer cells. First, we investigated the effects of both FPs on cell viability and induction of cell death in breast cancer cells and benign MCF-10A cells by XTT and DNA fragmentation assays, respectively. Morphological changes in human breast cancer cells after FPs treatment were detected by both phase contrast microscope and atomic force microscopy (AFM). Then, we tested whether FPs exert their cytotoxic effect through inhibiting PI3K/Akt and/or ERK1/2 signaling pathways by using specific inhibitors. Both FPs induced cytotoxicity in a time and concentration-dependent manner in breast cancer cells; however, MCF-10A benign breast epithelial cells were much less susceptible to the cytotoxic effect of both FPs. FPs inhibited both PI3K/Akt and ERK 1/2 signaling pathways in breast cancer cells. The ultra structure images of MCF-7 cells by AFM showed that the cell surface was smooth in untreated cells, but it was rough with protrusions in treated cells. Both FPs induced apoptotic cell death in MDA-MB-231 cells; however, necrotic cell death was induced in caspase-3 lack MCF-7 cells, which implies that the synthesized FPs may induce apoptosis through caspase-3 dependent mechanism. In summary, these results suggest that FPs might be promising agents for the breast cancer therapy.
authors.affiliation: Department of Biology, Section of Molecular Biology, Faculty of Science and Letters, Celal Bayar University, 45140 Manisa, Turkey. Electronic address: harika.atmaca@cbu.edu.tr.
authors.forename: Harika
authors.initials: H
authors.lastname: Atmaca
authors.affiliation: Applied Science Research Center, Celal Bayar University, 45140 Manisa, Turkey. Electronic address: aysenur.ozkan@cbu.edu.tr.
authors.forename: Ayşe Nur
authors.initials: AN
authors.lastname: Özkan
authors.affiliation: Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey. Electronic address: zora@metu.edu.tr.
authors.forename: Metin
authors.initials: M
authors.lastname: Zora
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005296:Ferrous Compounds / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D000075163:Metallocenes; D018625:Microscopy, Atomic Force; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D005296:Ferrous Compounds; D000075163:Metallocenes; D011720:Pyrazoles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; C004998:ferrocene
keywords: Apoptosis; Cell viability; ERK1/2; Ferrocene; Necrosis; PI3K/Akt; Pyrazole