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 (Ul-Mel) cell line, (d) does not synergistically potentiate melphalan-induced lethality against Ul-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 topoisomer-ase I derived from avian erythrocytes, calf thymus, or HEp-2 cells. β- Lapachone did not intercalate into DNA, nor did it inhibit topoisomerase II or ligation carried out by mammalian or T4 DNA ligases. Structurally similar analogues, a-lapachone, lapachol, and dichloroallyl lawsone, did not enhance X-ray-induced cytotoxicity nor did they activate topoisom-erase 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 ceUs was inhibited when β-lapachone was given immediately following or during X-irradia-tion. The effect decreased when the drug was added at later times. 0- 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 language||English (US)|
|Number of pages||8|
|State||Published - Feb 1 1989|
ASJC Scopus subject areas
- Cancer Research