Inhibition of potentially lethal DNA damage repair in human tumor cells by β-lapachone, an activator of topoisomerase I

D. A. Boothman, D. K. Trask, A. B. Pardee

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

A 4-h posttreatment with 4 μM β-lapachone was previously shown to enhance the lethality of X-rays against human laryngeal epidermoid carcinoma (HEp-2) cells (D.A. Boothman et al., Cancer Res., 47: 5361-5366, 1988). We now show that β-lapachone (a) activates the DNA-unwinding activity of topoisomerase I, (b) inhibits the fast component of potentially lethal damage repair (PLDR) carried out by HEp-2 cells when present during or immediately following X-irradiation, (c) specifically and synergistically enhances the cytotoxic effects of DNA-damaging agents which induce DNA strand incisions, such as neocarzinostatin or X-rays, against a radioresistant human malignant melanoma (U1-Mel) cell line, (d) does not syngergistically potentiate melphalan-induced lethality against U1-Mel cells but inhibits survival recovery and increases sister chromatid exchanges, and (e) does not further enhance the lethal effects of X-rays following prolonged drug exposures, indicating that β-lapachone modifies initially created DNA lesions or inhibits lesion repair but does not create lethal lesions by itself. β-Lapachone accelerated the DNA-unwinding activity of topoisomerase I derived from avian erythrocytes, calf thymus, or HEp-2 cells. β-Lapachone did not intercalate into DNA, nor did it inihbit topoisomerase II or ligation carried out by mammalian or T4 DNA ligases. Structurally similar analogues, α-lapachone, lapachol, and dichloroallyl lawsone, did not enhance X-ray-induced cytotoxicity nor did they activate topoisomerase I. Camptothecin, a specific inhibitor of topoisomerase I, significantly radiosensitized HEp-2 cells, in a manner similar to β-lapachone. These results suggest a role of topoisomerase I in DNA repair. The PLDR capacity of confluent-arrested HEp-2 cells was inhibited when β-lapachone was given immediately following or during X-irradiation. The effect decreased when the drug was added at later times. β-Lapachone may enhance lethality by converting single- into double-stranded DNA breaks during PLDR or through DNA conformational changes which inhibit PLDR. We propose that either mechanism of enhanced lethality may result from the ability of β-lapachone to activate topoisomerase I.

Original languageEnglish (US)
Pages (from-to)605-612
Number of pages8
JournalCancer Research
Volume49
Issue number3
StatePublished - 1989

Fingerprint

Type I DNA Topoisomerase
DNA Repair
DNA Damage
DNA
Neoplasms
X-Rays
lapachol
dichloroallyl lawsone
Zinostatin
Topoisomerase I Inhibitors
DNA Ligases
Camptothecin
Type II DNA Topoisomerase
Sister Chromatid Exchange
Melphalan
Double-Stranded DNA Breaks
Pharmaceutical Preparations
Thymus Gland
Ligation
Squamous Cell Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of potentially lethal DNA damage repair in human tumor cells by β-lapachone, an activator of topoisomerase I. / Boothman, D. A.; Trask, D. K.; Pardee, A. B.

In: Cancer Research, Vol. 49, No. 3, 1989, p. 605-612.

Research output: Contribution to journalArticle

Boothman, D. A. ; Trask, D. K. ; Pardee, A. B. / Inhibition of potentially lethal DNA damage repair in human tumor cells by β-lapachone, an activator of topoisomerase I. In: Cancer Research. 1989 ; Vol. 49, No. 3. pp. 605-612.
@article{c532b8a382884980970d3c0ad52bb354,
title = "Inhibition of potentially lethal DNA damage repair in human tumor cells by β-lapachone, an activator of topoisomerase I",
abstract = "A 4-h posttreatment with 4 μM β-lapachone was previously shown to enhance the lethality of X-rays against human laryngeal epidermoid carcinoma (HEp-2) cells (D.A. Boothman et al., Cancer Res., 47: 5361-5366, 1988). We now show that β-lapachone (a) activates the DNA-unwinding activity of topoisomerase I, (b) inhibits the fast component of potentially lethal damage repair (PLDR) carried out by HEp-2 cells when present during or immediately following X-irradiation, (c) specifically and synergistically enhances the cytotoxic effects of DNA-damaging agents which induce DNA strand incisions, such as neocarzinostatin or X-rays, against a radioresistant human malignant melanoma (U1-Mel) cell line, (d) does not syngergistically potentiate melphalan-induced lethality against U1-Mel cells but inhibits survival recovery and increases sister chromatid exchanges, and (e) does not further enhance the lethal effects of X-rays following prolonged drug exposures, indicating that β-lapachone modifies initially created DNA lesions or inhibits lesion repair but does not create lethal lesions by itself. β-Lapachone accelerated the DNA-unwinding activity of topoisomerase I derived from avian erythrocytes, calf thymus, or HEp-2 cells. β-Lapachone did not intercalate into DNA, nor did it inihbit topoisomerase II or ligation carried out by mammalian or T4 DNA ligases. Structurally similar analogues, α-lapachone, lapachol, and dichloroallyl lawsone, did not enhance X-ray-induced cytotoxicity nor did they activate topoisomerase I. Camptothecin, a specific inhibitor of topoisomerase I, significantly radiosensitized HEp-2 cells, in a manner similar to β-lapachone. These results suggest a role of topoisomerase I in DNA repair. The PLDR capacity of confluent-arrested HEp-2 cells was inhibited when β-lapachone was given immediately following or during X-irradiation. The effect decreased when the drug was added at later times. β-Lapachone may enhance lethality by converting single- into double-stranded DNA breaks during PLDR or through DNA conformational changes which inhibit PLDR. We propose that either mechanism of enhanced lethality may result from the ability of β-lapachone to activate topoisomerase I.",
author = "Boothman, {D. A.} and Trask, {D. K.} and Pardee, {A. B.}",
year = "1989",
language = "English (US)",
volume = "49",
pages = "605--612",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Inhibition of potentially lethal DNA damage repair in human tumor cells by β-lapachone, an activator of topoisomerase I

AU - Boothman, D. A.

AU - Trask, D. K.

AU - Pardee, A. B.

PY - 1989

Y1 - 1989

N2 - A 4-h posttreatment with 4 μM β-lapachone was previously shown to enhance the lethality of X-rays against human laryngeal epidermoid carcinoma (HEp-2) cells (D.A. Boothman et al., Cancer Res., 47: 5361-5366, 1988). We now show that β-lapachone (a) activates the DNA-unwinding activity of topoisomerase I, (b) inhibits the fast component of potentially lethal damage repair (PLDR) carried out by HEp-2 cells when present during or immediately following X-irradiation, (c) specifically and synergistically enhances the cytotoxic effects of DNA-damaging agents which induce DNA strand incisions, such as neocarzinostatin or X-rays, against a radioresistant human malignant melanoma (U1-Mel) cell line, (d) does not syngergistically potentiate melphalan-induced lethality against U1-Mel cells but inhibits survival recovery and increases sister chromatid exchanges, and (e) does not further enhance the lethal effects of X-rays following prolonged drug exposures, indicating that β-lapachone modifies initially created DNA lesions or inhibits lesion repair but does not create lethal lesions by itself. β-Lapachone accelerated the DNA-unwinding activity of topoisomerase I derived from avian erythrocytes, calf thymus, or HEp-2 cells. β-Lapachone did not intercalate into DNA, nor did it inihbit topoisomerase II or ligation carried out by mammalian or T4 DNA ligases. Structurally similar analogues, α-lapachone, lapachol, and dichloroallyl lawsone, did not enhance X-ray-induced cytotoxicity nor did they activate topoisomerase I. Camptothecin, a specific inhibitor of topoisomerase I, significantly radiosensitized HEp-2 cells, in a manner similar to β-lapachone. These results suggest a role of topoisomerase I in DNA repair. The PLDR capacity of confluent-arrested HEp-2 cells was inhibited when β-lapachone was given immediately following or during X-irradiation. The effect decreased when the drug was added at later times. β-Lapachone may enhance lethality by converting single- into double-stranded DNA breaks during PLDR or through DNA conformational changes which inhibit PLDR. We propose that either mechanism of enhanced lethality may result from the ability of β-lapachone to activate topoisomerase I.

AB - A 4-h posttreatment with 4 μM β-lapachone was previously shown to enhance the lethality of X-rays against human laryngeal epidermoid carcinoma (HEp-2) cells (D.A. Boothman et al., Cancer Res., 47: 5361-5366, 1988). We now show that β-lapachone (a) activates the DNA-unwinding activity of topoisomerase I, (b) inhibits the fast component of potentially lethal damage repair (PLDR) carried out by HEp-2 cells when present during or immediately following X-irradiation, (c) specifically and synergistically enhances the cytotoxic effects of DNA-damaging agents which induce DNA strand incisions, such as neocarzinostatin or X-rays, against a radioresistant human malignant melanoma (U1-Mel) cell line, (d) does not syngergistically potentiate melphalan-induced lethality against U1-Mel cells but inhibits survival recovery and increases sister chromatid exchanges, and (e) does not further enhance the lethal effects of X-rays following prolonged drug exposures, indicating that β-lapachone modifies initially created DNA lesions or inhibits lesion repair but does not create lethal lesions by itself. β-Lapachone accelerated the DNA-unwinding activity of topoisomerase I derived from avian erythrocytes, calf thymus, or HEp-2 cells. β-Lapachone did not intercalate into DNA, nor did it inihbit topoisomerase II or ligation carried out by mammalian or T4 DNA ligases. Structurally similar analogues, α-lapachone, lapachol, and dichloroallyl lawsone, did not enhance X-ray-induced cytotoxicity nor did they activate topoisomerase I. Camptothecin, a specific inhibitor of topoisomerase I, significantly radiosensitized HEp-2 cells, in a manner similar to β-lapachone. These results suggest a role of topoisomerase I in DNA repair. The PLDR capacity of confluent-arrested HEp-2 cells was inhibited when β-lapachone was given immediately following or during X-irradiation. The effect decreased when the drug was added at later times. β-Lapachone may enhance lethality by converting single- into double-stranded DNA breaks during PLDR or through DNA conformational changes which inhibit PLDR. We propose that either mechanism of enhanced lethality may result from the ability of β-lapachone to activate topoisomerase I.

UR - http://www.scopus.com/inward/record.url?scp=0024532122&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024532122&partnerID=8YFLogxK

M3 - Article

C2 - 2535961

AN - SCOPUS:0024532122

VL - 49

SP - 605

EP - 612

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 3

ER -