title: Influence of selected anti-cancer drugs on the induction of DNA double-strand breaks and changes in gene expression in human hepatoma HepG2 cells.
abstract: In chemotherapy, various anti-cancer drugs with different mechanisms of action are used and may represent different risk of undesirable delayed side effects in treated patients as well as in occupationally exposed populations. The aim of the present study was to evaluate genotoxic potential of four widely used anti-cancer drugs with different mechanisms of action: 5-fluorouracil (5-FU), cisplatin (CDDP) and etoposide (ET) that cause cell death by targeting DNA function and imatinib mesylate (IM) that inhibits targeted protein kinases in cancer cells in an experimental model with human hepatoma HepG2 cells. After 24 h of exposure all four anti-cancer drugs at non-cytotoxic concentrations induced significant increase in formation of DNA double strand breaks (DSBs), with IM being the least effective. The analysis of the changes in the expression of genes involved in the response to DNA damage (CDKN1A, GADD45A, MDM2), apoptosis (BAX, BCL2) and oncogenesis (MYC, JUN) showed that 5-FU, CDDP and ET upregulated the genes involved in DNA damage response, while the anti-apoptotic gene BCL2 and oncogene MYC were downregulated. On the contrary, IM did not change the mRNA level of the studied genes, showing different mechanism of action that probably does not involve direct interaction with DNA processing. Genotoxic effects of the tested anti-cancer drugs were observed at their therapeutic concentrations that may consequently lead to increased risk for development of delayed adverse effects in patients. In addition, considering the genotoxic mechanism of action of 5-FU, CDDP and ET an increased risk can also not be excluded in occupationally exposed populations. The results also indicate that exposure to 5-FU, CDDP and ET represent a higher risk for delayed effects such as cancer, reproductive effects and heritable disease than exposure to IM.
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia.|Ecological Engineering Institute, Maribor, Slovenia.|Jozef Stefan International Postgraduate School, Ljubljana, Slovenia.
authors.forename: Matjaž
authors.initials: M
authors.lastname: Novak
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia.
authors.forename: Bojana
authors.initials: B
authors.lastname: Žegura
authors.affiliation: Department of Biotechnology and System Biology, National Institute of Biology, Ljubljana, Slovenia.
authors.forename: Špela
authors.initials: Š
authors.lastname: Baebler
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia.
authors.forename: Alja
authors.initials: A
authors.lastname: Štern
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia.
authors.forename: Ana
authors.initials: A
authors.lastname: Rotter
authors.affiliation: Department of Biotechnology and System Biology, National Institute of Biology, Ljubljana, Slovenia.
authors.forename: Katja
authors.initials: K
authors.lastname: Stare
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia. metka.filipic@nib.si.
authors.forename: Metka
authors.initials: M
authors.lastname: Filipič
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D009152:Mutagenicity Tests
chemical_list: D000970:Antineoplastic Agents
keywords: Anti-cancer drugs; Gene expression; Genotoxicity; H2AX; HepG2 cells; Therapeutic concentrations