Inhibition of radiation-induced neoplastic transformation by β-lapachone

D. A. Boothman, A. B. Pardee

Research output: Contribution to journalArticle

69 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)4963-4967
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume86
Issue number13
StatePublished - 1989

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DNA Repair
DNA Damage
Radiation
Type I DNA Topoisomerase
Anticarcinogenic Agents
Single-Stranded DNA Breaks
DNA Breaks
Serum-Free Culture Media
Ionizing Radiation

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

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 journalArticle

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