Inhibition of radiation-induced neoplastic transformation by beta-lapachone.
Beta-lapachone is a potent inhibitor of DNA repair in mammalian cells and activates topoisomerase I. We show that beta-lapachone can prevent the oncogenic transformation of CHEF/18A cells by ionizing radiation. Potentially lethal DNA damage repair (PLDR) occurs while x-irradiated cells are held in medium containing low serum prior to replating. PLDR processes permitted survival recovery but also drastically increased the number of foci per plate (i.e., transformation) of CHEF/18A cells. By blocking PLDR with beta-lapachone, both survival recovery and enhanced transformation were prevented. At equivalent survival levels, exposure of x-irradiated cells to beta-lapachone resulted in an 8-fold decrease in the number of foci per dish as compared to the number of transformants produced after PLDR. Early PLDR-derived increases in transformation may be the result of error-prone genetic rearrangements dependent on topoisomerase I, which are thereby prevented by beta-lapachone. Beta-lapachone exposure decreased the rejoining of DNA strand breaks and produced additional double-strand breaks in x-irradiated cells during PLDR. The activation of topoisomerase I by beta-lapachone may convert repairable single-strand DNA breaks into the more repair-resistant double-strand breaks, thereby preventing PLDR and neoplastic transformation. These results suggest a new direction for the development of anticarcinogenic agents.
Boothman
D A
DA
Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, Boston, MA.
Pardee
A B
AB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004307:Dose-Response Relationship, Radiation; D009285:Naphthoquinones / Q000494:pharmacology*; D014965:X-Rays
D000903:Antibiotics, Antineoplastic; D009285:Naphthoquinones; C014638:beta-lapachone