Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1993 Jan;67(1):81–87. doi: 10.1038/bjc.1993.13

pH dependent cytotoxicity of N-dodecylimidazole: a compound that acquires detergent properties under acidic conditions.

M J Boyer 1, I Horn 1, R A Firestone 1, D Steele-Norwood 1, I F Tannock 1
PMCID: PMC1968209  PMID: 8427783

Abstract

N-dodecylimidazole is a compound which acquires detergent properties under acidic conditions and might be useful in killing selectively cells in those regions of solid tumours which have a reduced extracellular pH (pHe). We have therefore studied the effects of N-dodecylimidazole against malignant cells in tissue culture. N-dodecylimidazole displayed pHe-dependent cytotoxicity against EMT-6 and MGH U1 cells; cell killing was dose dependent and was 100-fold greater at pHe 6.0 than pHe 7.0. Reduced toxicity of N-dodecylimidazole was observed at higher cell concentrations (> 10(6) cells ml-1), and only minor effects were observed against multicellular tumour spheroids. Potential mechanisms of action of N-dodecylimidazole include detergent-mediated lysis of the cell membrane at low pHe, and selective uptake into lysosomes where detergent activity leads to rupture of the lysosomal membrane and release of cytolytic enzymes. Inhibition of activity of cysteine proteases by the inhibitor E-64 did not protect cells against the toxicity of N-dodecylimidazole, suggesting that these lysosomal enzymes do not play a major role in the mechanism of action of this compound. Lysis of erythrocytes (which contain no lysosomes) was observed with low concentrations of N-dodecylimidazole. Dependence of cell lysis on cell concentration was similar to that observed for two other detergents that act on the plasma membrane, Triton X-100 and sodium dodecyl sulfate. We conclude that N-dodecylimidazole causes pHe dependent cell killing in two cultured tumour cell lines, and that its mechanism of action is probably due to acid mediated production of detergent activity which acts primarily on the cell plasma membrane.

Full text

PDF
81

Selected References

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

  1. Barrett A. J., Kembhavi A. A., Brown M. A., Kirschke H., Knight C. G., Tamai M., Hanada K. L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L. Biochem J. 1982 Jan 1;201(1):189–198. doi: 10.1042/bj2010189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Coleman R. Membrane-bound enzymes and membrane ultrastructure. Biochim Biophys Acta. 1973 Apr 3;300(1):1–30. doi: 10.1016/0304-4157(73)90010-5. [DOI] [PubMed] [Google Scholar]
  3. Firestone R. A., Pisano J. M., Bonney R. J. Lysosomotropic agents. 1. Synthesis and cytotoxic action of lysosomotropic detergents. J Med Chem. 1979 Sep;22(9):1130–1133. doi: 10.1021/jm00195a026. [DOI] [PubMed] [Google Scholar]
  4. Forster S., Scarlett L., Lloyd J. B. The effect of lysosomotropic detergents on the permeability properties of the lysosome membrane. Biochim Biophys Acta. 1987 Jun 22;924(3):452–457. doi: 10.1016/0304-4165(87)90160-7. [DOI] [PubMed] [Google Scholar]
  5. Helenius A., Simons K. Solubilization of membranes by detergents. Biochim Biophys Acta. 1975 Mar 25;415(1):29–79. doi: 10.1016/0304-4157(75)90016-7. [DOI] [PubMed] [Google Scholar]
  6. Juliano R. L., Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta. 1976 Nov 11;455(1):152–162. doi: 10.1016/0005-2736(76)90160-7. [DOI] [PubMed] [Google Scholar]
  7. Kagawa Y. Reconstitution of oxidative phosphorylation. Biochim Biophys Acta. 1972 Aug 4;265(3):297–338. [PubMed] [Google Scholar]
  8. Miller D. K., Griffiths E., Lenard J., Firestone R. A. Cell killing by lysosomotropic detergents. J Cell Biol. 1983 Dec;97(6):1841–1851. doi: 10.1083/jcb.97.6.1841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Mohindra J. K., Rauth A. M. Increased cell killing by metronidazole and nitrofurazone of hypoxic compared to aerobic mammalian cells. Cancer Res. 1976 Mar;36(3):930–936. [PubMed] [Google Scholar]
  10. Neufeld E. F., Lim T. W., Shapiro L. J. Inherited disorders of lysosomal metabolism. Annu Rev Biochem. 1975;44:357–376. doi: 10.1146/annurev.bi.44.070175.002041. [DOI] [PubMed] [Google Scholar]
  11. Sutherland R. M. Cell and environment interactions in tumor microregions: the multicell spheroid model. Science. 1988 Apr 8;240(4849):177–184. doi: 10.1126/science.2451290. [DOI] [PubMed] [Google Scholar]
  12. Tannock I. F., Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 1989 Aug 15;49(16):4373–4384. [PubMed] [Google Scholar]
  13. Wiesmann U. N., Herschkowitz N. N. Studies on the pathogenetic mechanism of I-cell disease in cultured fibroblasts. Pediatr Res. 1974 Nov;8(11):865–869. doi: 10.1203/00006450-197411000-00002. [DOI] [PubMed] [Google Scholar]
  14. Wike-Hooley J. L., Haveman J., Reinhold H. S. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol. 1984 Dec;2(4):343–366. doi: 10.1016/s0167-8140(84)80077-8. [DOI] [PubMed] [Google Scholar]
  15. Williams G. M., Stromberg K., Krodes R. Cytochemical and ultrastructural alterations associated with confluent growth in cell cultures of epithelial-like cells from rat liver. Lab Invest. 1973 Sep;29(3):293–303. [PubMed] [Google Scholar]
  16. Wilson P. D., Firestone R. A., Lenard J. The role of lysosomal enzymes in killing of mammalian cells by the lysosomotropic detergent N-dodecylimidazole. J Cell Biol. 1987 May;104(5):1223–1229. doi: 10.1083/jcb.104.5.1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Wilson P. D., Hreniuk D., Lenard J. A relationship between multidrug resistance and growth-state dependent cytotoxicity of the lysosomotropic detergent N-dodecylimidazole. Biochem Biophys Res Commun. 1991 May 15;176(3):1377–1382. doi: 10.1016/0006-291x(91)90439-e. [DOI] [PubMed] [Google Scholar]
  18. Wilson P. D., Hreniuk D., Lenard J. Reduced cytotoxicity of the lysosomotropic detergent N-dodecylimidazole after differentiation of HL60 promyelocytes. Cancer Res. 1989 Feb 1;49(3):507–510. [PubMed] [Google Scholar]

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

RESOURCES