title: Susceptibility of cancer cells to beta-lapachone is enhanced by ionizing radiation.
abstract: OBJECTIVE
  To reveal the interaction between beta-lapachone (beta-lap) and ionizing radiation (IR) in causing clonogenic death in cancer cells and to elucidate the potential usefulness of beta-lap treatment in combination with radiotherapy of cancer.
  
  
  METHODS
  FSaII tumor cells of C3H mice were used. The cytotoxicity of beta-lap alone or in combination with IR in vitro was determined using clonogenic survival assay method. The IR-induced changes in the expression and the enzymatic activity of NAD(P)H:quinone oxidoreductase (NQO1), a mediator of beta-lap cytotoxicity, were elucidated and the relationship between the NQO1 level and the sensitivity of cells to beta-lap was investigated. The combined effect of IR and beta-lap to suppress tumor growth was studied using FSaII tumors grown subcutaneously in the thigh of C3H mice.
  
  
  RESULTS
  beta-Lap caused clonogenic death of FSaII tumor cells in vitro in a dose- and time-dependent manner. When cells were treated first with beta-lap and then exposed to IR in vitro, the resultant cell death was only additive. On the contrary, exposing cells to IR at 2.5 Gy first and then treating the cells with beta-lap killed the cells in a synergistic manner. Importantly, the 2.5 Gy cells were sensitive to beta-lap as long as 10 h after irradiation, which was long after the sublethal radiation damage was repaired. Irradiation of FSaII cells in vitro with 2.5 Gy significantly increased the expression and enzymatic activity of NQO1. The growth delay of FSaII tumors caused by an intraperitoneal injection of beta-lap in combination with 20 Gy irradiation of tumor was significantly greater than that caused by beta-lap or 20 Gy irradiation alone.
  
  
  CONCLUSIONS
  The sensitivity of cells to beta-lap is dependent on NQO1 activity. IR caused a long-lasting increase in NQO1 activity in cancer cells, thereby sensitizing cells to beta-lap and treatment of experimental mouse tumors with IR and beta-lap suppressed tumor growth in a synergistic manner. The combination of beta-lap and radiotherapy is a potentially effective regimen for the treatment of human cancer.
authors.affiliation: Radiobiology Laboratory, Department of Therapeutic Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. chaex001@umn.edu
authors.forename: Heon Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Ki-Jung
authors.initials: KJ
authors.lastname: Ahn
authors.forename: Seung-Do
authors.initials: SD
authors.lastname: Ahn
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Choi
authors.forename: Sang Wook
authors.initials: SW
authors.lastname: Lee
authors.forename: Brent
authors.initials: B
authors.lastname: Williams
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Robert
authors.initials: R
authors.lastname: Griffin
authors.forename: Erik A
authors.initials: EA
authors.lastname: Bey
authors.forename: William G
authors.initials: WG
authors.lastname: Bornmann
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
authors.forename: Heon Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.forename: Chang W
authors.initials: CW
authors.lastname: Song
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D001728:Dicumarol / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000528:radiation effects; D009285:Naphthoquinones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000528:radiation effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; C014638:beta-lapachone; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human