Abstract
β-Lapachone is a potent inhibitor of DNA repair in mammalian cells and activates topoisomerase I. We show that β-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 replacing. 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 β-lapachone, both survival recovery and enhanced transformation were prevented. At equivalent survival levels, exposure of x-irradiated cells to β-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 β-lapachone. β-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 β-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4963-4967 |
| Number of pages | 5 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 86 |
| Issue number | 13 |
| State | Published - 1989 |
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ASJC Scopus subject areas
- General
- Genetics
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Inhibition of radiation-induced neoplastic transformation by β-lapachone. / Boothman, D. A.; Pardee, A. B.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 86, No. 13, 1989, p. 4963-4967.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of radiation-induced neoplastic transformation by β-lapachone
AU - Boothman, D. A.
AU - Pardee, A. B.
PY - 1989
Y1 - 1989
N2 - β-Lapachone is a potent inhibitor of DNA repair in mammalian cells and activates topoisomerase I. We show that β-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 replacing. 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 β-lapachone, both survival recovery and enhanced transformation were prevented. At equivalent survival levels, exposure of x-irradiated cells to β-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 β-lapachone. β-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 β-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.
AB - β-Lapachone is a potent inhibitor of DNA repair in mammalian cells and activates topoisomerase I. We show that β-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 replacing. 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 β-lapachone, both survival recovery and enhanced transformation were prevented. At equivalent survival levels, exposure of x-irradiated cells to β-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 β-lapachone. β-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 β-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.
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M3 - Article
VL - 86
SP - 4963
EP - 4967
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 13
ER -