Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Nov;81(5):796–799. doi: 10.1038/sj.bjc.6690766

Arsenic trioxide sensitivity is associated with low level of glutathione in cancer cells

C-H Yang 1,2, M-L Kuo 3, J-C Chen 1, Y-C Chen 4
PMCID: PMC2374294  PMID: 10555748

Abstract

Arsenic trioxide (As2O3) is a novel anticancer agent, which has been found to induce remission in acute promyelocytic leukaemic patients following daily intravenous administration. The therapeutic value of As2O3 in other cancers is still largely unknown. Cytotoxic tests in a panel of cancer cell lines showed that bladder cancer, acute promyelocytic leukaemic and gastrointestinal cancer cells were the most sensitive to As2O3 among 17 cell lines tested. Cellular glutathione (GSH) system plays an important role in arsenic detoxification in mammalian cells. Cancer cells that were intrinsically sensitive to As2O3 contained lower levels of GSH, whereas resistant cancer cells contained higher levels of GSH. On the other hand, there was no association of glutathione-S-transferase-π or multidrug resistance-associated protein 1 levels with arsenic sensitivity in these cancer cells. Multidrug-resistant cancer cells that were cross-resistant to arsenic contained higher levels of GSH or multidrug-resistance-associated protein 1 than their drug-sensitive parental cells. Cancer cells become more sensitive to arsenic after depletion of cellular GSH with L-buthionine sulphoximine. We concluded that cellular GSH level is the most important determinant of arsenic sensitivity in cancer cells. Cellular GSH level and its modulation by buthionine sulphoximine should be considered in designing clinical trials using arsenic in solid tumours. © 1999 Cancer Research Campaign

Keywords: arsenic trioxide, glutathione, buthionine sulphoximine

Full Text

The Full Text of this article is available as a PDF (76.1 KB).

Selected References

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

  1. Bailey H. H., Mulcahy R. T., Tutsch K. D., Arzoomanian R. Z., Alberti D., Tombes M. B., Wilding G., Pomplun M., Spriggs D. R. Phase I clinical trial of intravenous L-buthionine sulfoximine and melphalan: an attempt at modulation of glutathione. J Clin Oncol. 1994 Jan;12(1):194–205. doi: 10.1200/JCO.1994.12.1.194. [DOI] [PubMed] [Google Scholar]
  2. Chen G. Q., Shi X. G., Tang W., Xiong S. M., Zhu J., Cai X., Han Z. G., Ni J. H., Shi G. Y., Jia P. M. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood. 1997 May 1;89(9):3345–3353. [PubMed] [Google Scholar]
  3. Cole S. P., Sparks K. E., Fraser K., Loe D. W., Grant C. E., Wilson G. M., Deeley R. G. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 1994 Nov 15;54(22):5902–5910. [PubMed] [Google Scholar]
  4. Flens M. J., Izquierdo M. A., Scheffer G. L., Fritz J. M., Meijer C. J., Scheper R. J., Zaman G. J. Immunochemical detection of the multidrug resistance-associated protein MRP in human multidrug-resistant tumor cells by monoclonal antibodies. Cancer Res. 1994 Sep 1;54(17):4557–4563. [PubMed] [Google Scholar]
  5. Gallagher R. E. Arsenic--new life for an old potion. N Engl J Med. 1998 Nov 5;339(19):1389–1391. doi: 10.1056/NEJM199811053391909. [DOI] [PubMed] [Google Scholar]
  6. Huang H., Huang C. F., Wu D. R., Jinn C. M., Jan K. Y. Glutathione as a cellular defence against arsenite toxicity in cultured Chinese hamster ovary cells. Toxicology. 1993 May 24;79(3):195–204. doi: 10.1016/0300-483x(93)90211-a. [DOI] [PubMed] [Google Scholar]
  7. König A., Wrazel L., Warrell R. P., Jr, Rivi R., Pandolfi P. P., Jakubowski A., Gabrilove J. L. Comparative activity of melarsoprol and arsenic trioxide in chronic B-cell leukemia lines. Blood. 1997 Jul 15;90(2):562–570. [PubMed] [Google Scholar]
  8. Lo J. F., Wang H. F., Tam M. F., Lee T. C. Glutathione S-transferase pi in an arsenic-resistant Chinese hamster ovary cell line. Biochem J. 1992 Dec 15;288(Pt 3):977–982. doi: 10.1042/bj2880977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Rappa G., Lorico A., Flavell R. A., Sartorelli A. C. Evidence that the multidrug resistance protein (MRP) functions as a co-transporter of glutathione and natural product toxins. Cancer Res. 1997 Dec 1;57(23):5232–5237. [PubMed] [Google Scholar]
  10. Schneider E., Horton J. K., Yang C. H., Nakagawa M., Cowan K. H. Multidrug resistance-associated protein gene overexpression and reduced drug sensitivity of topoisomerase II in a human breast carcinoma MCF7 cell line selected for etoposide resistance. Cancer Res. 1994 Jan 1;54(1):152–158. [PubMed] [Google Scholar]
  11. Scott N., Hatlelid K. M., MacKenzie N. E., Carter D. E. Reactions of arsenic(III) and arsenic(V) species with glutathione. Chem Res Toxicol. 1993 Jan-Feb;6(1):102–106. doi: 10.1021/tx00031a016. [DOI] [PubMed] [Google Scholar]
  12. Shen Z. X., Chen G. Q., Ni J. H., Li X. S., Xiong S. M., Qiu Q. Y., Zhu J., Tang W., Sun G. L., Yang K. Q. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997 May 1;89(9):3354–3360. [PubMed] [Google Scholar]
  13. Skehan P., Storeng R., Scudiero D., Monks A., McMahon J., Vistica D., Warren J. T., Bokesch H., Kenney S., Boyd M. R. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990 Jul 4;82(13):1107–1112. doi: 10.1093/jnci/82.13.1107. [DOI] [PubMed] [Google Scholar]
  14. Soignet S. L., Maslak P., Wang Z. G., Jhanwar S., Calleja E., Dardashti L. J., Corso D., DeBlasio A., Gabrilove J., Scheinberg D. A. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998 Nov 5;339(19):1341–1348. doi: 10.1056/NEJM199811053391901. [DOI] [PubMed] [Google Scholar]
  15. Tzeng C. C., Liu H. S., Li C., Jin Y. T., Chen R. M., Yang W. H., Lin J. S. Characterization of two urothelium cancer cell lines derived from a blackfoot disease endemic area in Taiwan. Anticancer Res. 1996 Jul-Aug;16(4A):1797–1804. [PubMed] [Google Scholar]
  16. Wang H. F., Lee T. C. Glutathione S-transferase pi facilitates the excretion of arsenic from arsenic-resistant Chinese hamster ovary cells. Biochem Biophys Res Commun. 1993 May 14;192(3):1093–1099. doi: 10.1006/bbrc.1993.1529. [DOI] [PubMed] [Google Scholar]
  17. Yu H. J., Tsai T. C., Hsieh T. S., Chiu T. Y. Characterization of a newly established human bladder carcinoma cell line, NTUB1. J Formos Med Assoc. 1992 Jun;91(6):608–613. [PubMed] [Google Scholar]

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

RESOURCES