Susceptibility of cancer cells to beta-lapachone is enhanced by ionizing radiation.
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.
Park
Heon Joo
HJ
Radiobiology Laboratory, Department of Therapeutic Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. chaex001@umn.edu
Ahn
Ki-Jung
KJ
Ahn
Seung-Do
SD
Choi
Eunkyung
E
Lee
Sang Wook
SW
Williams
Brent
B
Kim
Eun Jung
EJ
Griffin
Robert
R
Bey
Erik A
EA
Bornmann
William G
WG
Gao
Jinming
J
Park
Heon Jin
HJ
Boothman
David A
DA
Song
Chang W
CW
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*
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