title: Anticancer activity and radiosensitization effect of methyleneisoxazolidin-5-ones in hepatocellular carcinoma HepG2 cells.
abstract: Parthenolide (PTL), a well-known sesquiterpene lactone of natural origin with α,β-unsaturated carbonyl structure, has proven to show promising anti-cancer properties. In this report, anti-proliferative potential of two synthetic methyleneisoxazolidin-5-ones, MZ-6 and MZ-14, with the same structural motif, has been investigated in human hepatoma HepG2 cells. The effects on apoptosis induction and DNA damage were evaluated. All compounds decreased the number of live cells and increased the number of late apoptotic cells. However, only MZ-14 was able to induce DNA damage. Both synthetic compounds increased intracellular reactive oxygen species (ROS) generation and mitochondrial membrane potential changes at the same level as PTL. Additionally, cell survival was analyzed after a combined treatment, in which HepG2 cells were preincubated for 24 h with MZ-6, MZ-14 or PTL and irradiated with different doses of X-rays. The inhibition of cell survival was assessed by the clonogenic assay. We have shown that the clone formation was strongly inhibited by the combined treatment. The synergistic effect was observed for all three compounds but MZ-6 was significantly more effective. It is interesting to note that in HepG2 cells MZ-6 was the least cytotoxic of the tested compounds, did not induce DNA damage and was less active than the others in the clonogenic cell survival assay. It seems advantages from the point of view of the further in vivo studies that the compound with the lowest cytotoxic activity showed the strongest sensitizing effect.
authors: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
authors: Katarzyna
authors: K
authors: Gach
authors: Center for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland.
authors: Iwona
authors: I
authors: Grądzka
authors: Center for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland.
authors: Iwona
authors: I
authors: Wasyk
authors: Center for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland.
authors: Sylwia
authors: S
authors: Męczyńska-Wielgosz
authors: Center for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland.
authors: Teresa
authors: T
authors: Iwaneńko
authors: Central Scientific Laboratory, Division of Public Health, Faculty of Health Sciences, Medical University of Lodz, Lodz, Poland.
authors: Jacek
authors: J
authors: Szymański
authors: Institute of Organic Chemistry, Lodz University of Technology, Lodz, Poland.
authors: Jacek
authors: J
authors: Koszuk
authors: Institute of Organic Chemistry, Lodz University of Technology, Lodz, Poland.
authors: Tomasz
authors: T
authors: Janecki
authors: Center for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland; Faculty of Medicine, University of Information Technology and Management, Rzeszów, Poland.
authors: Marcin
authors: M
authors: Kruszewski
authors: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. Electronic address: anna.janecka@umed.lodz.pl.
authors: Anna
authors: A
authors: Janecka
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C571418:3-isopropyl-2-methyl-4-methyleneisoxazolidin-5-one; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D007555:Isoxazoles; C000609222:MZ-14 compound; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C002669:parthenolide
keywords: Anticancer agents; Apoptosis; HepG2; Integrated therapy; X-ray sensitization