Skip to main content
NCBI home page
The British Journal of Cancer. Supplement logoLink to The British Journal of Cancer. Supplement
. 1996 Jul;27:S23–S27.

Cytotoxic mechanisms of anti-tumour quinones in parental and resistant lymphoblasts.

A Halinska 1, T Belej 1, P J O'Brien 1
PMCID: PMC2150036  PMID: 8763840

Abstract

The group I aziridinylquinone anti-cancer agents mitomycin C, diaziquone or trenimon were much more cytotoxic to DT-diaphorase-enriched L5178Y/HBM10 lymphoblasts than parental L5178Y cells and caused little oxygen activation. Furthermore, inactivation of cellular DT-diaphorase prevented cytotoxicity whereas catalase did not affect cytotoxicity. This suggests that DT-diaphorase activated these agents and the hydroquinone formed mediated DNA alkylation, crosslinking and cytotoxicity. The group II quinone agents phenanthrenequinone, 2-amino-1, 4-naphthoquinoneimine or naphthazarin were also more cytotoxic to L5178Y/HBM10 cells than parental cells and caused considerable oxygen activation. Inactivation of DT-diaphorase, however, prevented both oxygen activation and cytotoxicity. Furthermore added catalase decreased cytotoxicity, whereas catalase inactivation enhanced cytotoxicity. This suggests that DT-diaphorase activated these agents and the hydroquinone formed caused extensive oxygen activation sufficient to cause DNA oxidative damage and cytotoxicity. The group III quinone agents menadione, 2,3-dimethoxy-1,4-naphthoquinone and 2,6-dimethoxy-benzoquinone, on the other hand, were more cytotoxic to the parental cells than L5178Y/HBM10 cells and caused less oxygen activation than group II agents. Furthermore, inactivation of DT-diaphorase enhanced cytotoxicity and prevented oxygen activation than group II agents. Oxygen activation was therefore also attributed to hydroquinone autoxidation. However catalase did not affect cytotoxicity towards parental cells. This suggests that DT-diaphorase detoxified group III quinones and that cytotoxicity may involve DNA oxidative damage by the semiquinone radicals.

Full text

PDF
S23

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beall H. D., Mulcahy R. T., Siegel D., Traver R. D., Gibson N. W., Ross D. Metabolism of bioreductive antitumor compounds by purified rat and human DT-diaphorases. Cancer Res. 1994 Jun 15;54(12):3196–3201. [PubMed] [Google Scholar]
  2. Begleiter A. Cytocidal action of the quinone group and its relationship to antitumor activity. Cancer Res. 1983 Feb;43(2):481–484. [PubMed] [Google Scholar]
  3. Begleiter A., Leith M. K. Activity of quinone alkylating agents in quinone-resistant cells. Cancer Res. 1990 May 15;50(10):2872–2876. [PubMed] [Google Scholar]
  4. Begleiter A., Leith M. K., McClarty G., Beenken S., Goldenberg G. J., Wright J. A. Characterization of L5178Y murine lymphoblasts resistant to quinone antitumor agents. Cancer Res. 1988 Apr 1;48(7):1727–1735. [PubMed] [Google Scholar]
  5. Begleiter A., Robotham E., Lacey G., Leith M. K. Increased sensitivity of quinone resistant cells to mitomycin C. Cancer Lett. 1989 Jun;45(3):173–176. doi: 10.1016/0304-3835(89)90073-6. [DOI] [PubMed] [Google Scholar]
  6. Cantoni O., Fiorani M., Cattabeni F., Bellomo G. DNA breakage caused by hydrogen peroxide produced during the metabolism of 2-methyl-1,4-naphthoquinone (menadione) does not contribute to the cytotoxic action of the quinone. Biochem Pharmacol. 1991 Dec 11;42 (Suppl):S220–S222. doi: 10.1016/0006-2952(91)90415-2. [DOI] [PubMed] [Google Scholar]
  7. Dwivedy I., Devanesan P., Cremonesi P., Rogan E., Cavalieri E. Synthesis and characterization of estrogen 2,3- and 3,4-quinones. Comparison of DNA adducts formed by the quinones versus horseradish peroxidase-activated catechol estrogens. Chem Res Toxicol. 1992 Nov-Dec;5(6):828–833. doi: 10.1021/tx00030a016. [DOI] [PubMed] [Google Scholar]
  8. Gant T. W., Rao D. N., Mason R. P., Cohen G. M. Redox cycling and sulphydryl arylation; their relative importance in the mechanism of quinone cytotoxicity to isolated hepatocytes. Chem Biol Interact. 1988;65(2):157–173. doi: 10.1016/0009-2797(88)90052-x. [DOI] [PubMed] [Google Scholar]
  9. Gibson N. W., Hartley J. A., Butler J., Siegel D., Ross D. Relationship between DT-diaphorase-mediated metabolism of a series of aziridinylbenzoquinones and DNA damage and cytotoxicity. Mol Pharmacol. 1992 Sep;42(3):531–536. [PubMed] [Google Scholar]
  10. Lind C., Hochstein P., Ernster L. DT-diaphorase as a quinone reductase: a cellular control device against semiquinone and superoxide radical formation. Arch Biochem Biophys. 1982 Jun;216(1):178–185. doi: 10.1016/0003-9861(82)90202-8. [DOI] [PubMed] [Google Scholar]
  11. Malkinson A. M., Siegel D., Forrest G. L., Gazdar A. F., Oie H. K., Chan D. C., Bunn P. A., Mabry M., Dykes D. J., Harrison S. D. Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin Cł. Cancer Res. 1992 Sep 1;52(17):4752–4757. [PubMed] [Google Scholar]
  12. Marshall R. S., Paterson M. C., Rauth A. M. DT-diaphorase activity and mitomycin C sensitivity in non-transformed cell strains derived from members of a cancer-prone family. Carcinogenesis. 1991 Jul;12(7):1175–1180. doi: 10.1093/carcin/12.7.1175. [DOI] [PubMed] [Google Scholar]
  13. Miller M. G., Rodgers A., Cohen G. M. Mechanisms of toxicity of naphthoquinones to isolated hepatocytes. Biochem Pharmacol. 1986 Apr 1;35(7):1177–1184. doi: 10.1016/0006-2952(86)90157-7. [DOI] [PubMed] [Google Scholar]
  14. Morgan W. A., Hartley J. A., Cohen G. M. Quinone-induced DNA single strand breaks in rat hepatocytes and human chronic myelogenous leukaemic K562 cells. Biochem Pharmacol. 1992 Jul 22;44(2):215–221. doi: 10.1016/0006-2952(92)90003-2. [DOI] [PubMed] [Google Scholar]
  15. Ngo E. O., Sun T. P., Chang J. Y., Wang C. C., Chi K. H., Cheng A. L., Nutter L. M. Menadione-induced DNA damage in a human tumor cell line. Biochem Pharmacol. 1991 Oct 24;42(10):1961–1968. doi: 10.1016/0006-2952(91)90596-w. [DOI] [PubMed] [Google Scholar]
  16. O'Brien P. J. Molecular mechanisms of quinone cytotoxicity. Chem Biol Interact. 1991;80(1):1–41. doi: 10.1016/0009-2797(91)90029-7. [DOI] [PubMed] [Google Scholar]
  17. Ollinger K., Buffinton G. D., Ernster L., Cadenas E. Effect of superoxide dismutase on the autoxidation of substituted hydro- and semi-naphthoquinones. Chem Biol Interact. 1990;73(1):53–76. doi: 10.1016/0009-2797(90)90108-y. [DOI] [PubMed] [Google Scholar]
  18. Pan S. S., Yu F., Hipsher C. Enzymatic and pH modulation of mitomycin C-induced DNA damage in mitomycin C-resistant HCT 116 human colon cancer cells. Mol Pharmacol. 1993 Jun;43(6):870–877. [PubMed] [Google Scholar]
  19. Pethig R., Gascoyne P. R., McLaughlin J. A., Szent-Györgyi A. Interaction of the 2,6-dimethoxysemiquinone and ascorbyl free radicals with Ehrlich ascites cells: a probe of cell-surface charge. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2088–2091. doi: 10.1073/pnas.81.7.2088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Powis G., Hodnett E. M., Santone K. S., See K. L., Melder D. C. Role of metabolism and oxidation-reduction cycling in the cytotoxicity of antitumor quinoneimines and quinonediimines. Cancer Res. 1987 May 1;47(9):2363–2370. [PubMed] [Google Scholar]
  21. Preusch P. C., Siegel D., Gibson N. W., Ross D. A note on the inhibition of DT-diaphorase by dicoumarol. Free Radic Biol Med. 1991;11(1):77–80. doi: 10.1016/0891-5849(91)90191-5. [DOI] [PubMed] [Google Scholar]
  22. Riley R. J., Workman P. DT-diaphorase and cancer chemotherapy. Biochem Pharmacol. 1992 Apr 15;43(8):1657–1669. doi: 10.1016/0006-2952(92)90694-e. [DOI] [PubMed] [Google Scholar]
  23. Rockwell S., Sartorelli A. C., Tomasz M., Kennedy K. A. Cellular pharmacology of quinone bioreductive alkylating agents. Cancer Metastasis Rev. 1993 Jun;12(2):165–176. doi: 10.1007/BF00689808. [DOI] [PubMed] [Google Scholar]
  24. Siegel D., Beall H., Senekowitsch C., Kasai M., Arai H., Gibson N. W., Ross D. Bioreductive activation of mitomycin C by DT-diaphorase. Biochemistry. 1992 Sep 1;31(34):7879–7885. doi: 10.1021/bi00149a019. [DOI] [PubMed] [Google Scholar]
  25. Silva J. M., O'Brien P. J. Molecular mechanisms of trenimon-induced cytotoxicity in resistant L5178Y/HBM10 cells. Int J Radiat Oncol Biol Phys. 1992;22(4):639–642. doi: 10.1016/0360-3016(92)90494-3. [DOI] [PubMed] [Google Scholar]
  26. Tsuda H. Role of DT diaphorase the cytotoxicity of menadione and 4-nitroquinoline-1-oxide in cultured mammalian fibroblastic cells. Cancer Lett. 1990 Dec 17;55(3):195–199. doi: 10.1016/0304-3835(90)90119-i. [DOI] [PubMed] [Google Scholar]
  27. Yoshida T., Tsuda H. Gene targeting of DT-diaphorase in mouse embryonic stem cells: establishment of null mutant and its mitomycin C-resistance. Biochem Biophys Res Commun. 1995 Sep 14;214(2):701–708. doi: 10.1006/bbrc.1995.2342. [DOI] [PubMed] [Google Scholar]

Articles from The British Journal of Cancer. Supplement are provided here courtesy of Cancer Research UK

RESOURCES