title: The Effect of Caffeine and chk2 Inhibitor on Doxorubicin-Induced Cellular Senescence in MCF-7 Cells.
abstract: Senescence is cellular growth arrest. Induction of senescence can be considered as an alternative approach for treating cancer cells being resistance to anti-cancer drugs. We investigated the effect of caffeine and chk2 inhibitor on doxorubicin induced senescence in MCF-7 cells. Caffeine and chk2 inhibitor were used in combination with doxorubicin. Cellular senescence was assessed by β-galactosidase assay. P21 expression was determined using immunoblotting. Cell proliferation was evaluated using prestoblue assay. Results revealed that doxorubicin induced senescence and increased p21 expression in MCF-7 cells. However, co-treatment of chk2 inhibitor and caffeine with doxorubicin could not augment doxorubicin-induced senescence. Moreover, p21 expression was decreased in combination studies compared to doxorubicin group. Our results indicate that caffeine, chk2 inhibitor and combination of chk2 inhibitor, caffeine and doxorubicin could not increase sensitivity of the cells to doxorubicin-induced senescence. Our findings demonstrate that low-dose doxorubicin induced senescence via the activation of ATM, -chk2, and -p21 pathways, while inhibition of ATM and chk2 cannot consider as a new target for sensitization of MCF-7 cells to doxorubicin. Thus, chk2 inhibitor and caffeine might not serve as desirable agents being capable to restore chemo sensitivity in doxorubicin-resistant breast tumors.
authors.affiliation: Department of Biology, Faculty of Sciences, University of Mazandaran, Babolsar, Iran.
authors.forename: F Mir
authors.initials: FM
authors.lastname: Mohammadrezaei
authors.affiliation: Department of Statistics, Faculty of Mathematical sciences, University of Mazandaran, Babolsar, Iran.
authors.forename: A Fayyaz
authors.initials: AF
authors.lastname: Movaghar
authors.affiliation: Department of Toxicology-Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: M
authors.initials: M
authors.lastname: Gharghabi
mesh_terms: D002110:Caffeine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D064447:Checkpoint Kinase 2 / Q000037:antagonists & inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004317:Doxorubicin / Q000037:antagonists & inhibitors*; D006801:Humans; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; D002110:Caffeine; D004317:Doxorubicin; D064447:Checkpoint Kinase 2; D001616:beta-Galactosidase