| Autor: |
Alves de Lima LV; Department of General Biology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., da Silva MF; Department of General Biology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Concato VM; Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Rondina DBL; Department of General Biology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Zanetti TA; Department of General Biology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Felicidade I; Department of General Biology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Areal Marques L; Department of General Biology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Lepri SR; Department of General Biology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Simionato AS; Department of Microbiology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Filho GA; Department of Microbiology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil., Coatti GC; Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA., Mantovani MS; Department of General Biology, Center of Biological Sciences, State University of Londrina, Paraná, Brazil. |
| Abstrakt: |
Fluopsin C is an antibiotic compound derived from secondary metabolism of different microorganisms, which possesses antitumor, antibacterial, and antifungal activity. Related to fluopsin C antiproliferative activity, the aim of this study was to examine the following parameters: cytotoxicity, genotoxicity, cell cycle arrest, cell death induction (apoptosis), mitochondrial membrane potential (MMP), colony formation, and mRNA expression of genes involved in adaptive stress responses and cellular death utilizing a monolayer. In addition, a three-dimensional cell culture was used to evaluate the effects on growth of tumor spheroids. Fluopsin C was cytotoxic (1) producing cell division arrest in the G 1 phase, (2) elevating expression of mRNA of the CDKN1A gene and (3) decrease in expression of mRNA H2AFX gene. Further, fluopsin C enhanced DNA damage as evidenced by increased expression of mRNA of GADD45A and GPX1 genes, indicating that reactive oxygen species (ROS) may be involved in the observed genotoxic response. Reticulum stress was also detected as noted from activation of the ribonuclease inositol-requiring protein 1 (IRE1) pathway, since a rise in mRNA expression of the ERN1 and TRAF2 genes was observed. During the cell death process, an increase in mRNA expression of the BBC3 gene was noted, indicating participation of this antibiotic in oncotic (ischemic) cell death. Data thus demonstrated for the first time that fluopsin C interferes with the volume of tumor spheroids, in order to attenuate their growth. Our findings show that fluopsin C modulates essential molecular processes in response to stress and cell death. |
