Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Aug 17;83(6):800–810. doi: 10.1054/bjoc.2000.1353

Single amino acid (arginine) deprivation: rapid and selective death of cultured transformed and malignant cells

L Scott 1, J Lamb 1, S Smith 1, D N Wheatley 1
PMCID: PMC2363527  PMID: 10952786

Abstract

The effects of arginine deprivation (–Arg) has been examined in 26 cell lines. Less than 10% of those with transformed or malignant phenotype survived for > 5 days, and many died more rapidly, notably leukaemic cells. Bivariate flow cytometry confirmed that vulnerable cell lines failed to move out of cell cycle into a quiescent state (G0), but reinitiated DNA synthesis. Many cells remained in S-phase, and/or had difficulty progressing through to G2 and M. Two tumour lines proved relatively ‘resistant’, A549 and MCF7. Although considerable cell loss occurred initially, both lines showed a ‘cell cycle freeze’, in which cells survived for > 10 days. These cells recovered their proliferative activity in +Arg medium, but behaved in the same manner to a second –Arg episode as they did to the first episode. In contrast, normal cells entered G0 and survived in –Arg medium for several weeks, with the majority of cells recovering with predictable kinetics in +Arg medium. In general, cells from a wide range of tumours and established lines die quickly in vitro following –Arg treatment, because of defective cell cycle checkpoint stringency, the efficacy of the treatment being most clearly demonstrated in co-cultures in which only the normal cells survived. The findings demonstrate a potentially simple, effective and non-genotoxic strategy for the treatment of a wide range of cancers. © 2000 Cancer Research Campaign

Keywords: arginine, growth, death, malignant cells, normal cells

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

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

  1. Ando K., Griffin J. D. Cdk4 integrates growth stimulatory and inhibitory signals during G1 phase of hematopoietic cells. Oncogene. 1995 Feb 16;10(4):751–755. [PubMed] [Google Scholar]
  2. BACH S. J., SWAINE D. THE EFFECT OF ARGINASE ON THE RETARDATION OF TUMOUR GROWTH. Br J Cancer. 1965 Jun;19:379–386. doi: 10.1038/bjc.1965.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brittenden J., Heys S. D., Eremin O. L-arginine and malignant disease: a potential therapeutic role? Eur J Surg Oncol. 1994 Apr;20(2):189–192. [PubMed] [Google Scholar]
  4. Dolbeare F., Gratzner H., Pallavicini M. G., Gray J. W. Flow cytometric measurement of total DNA content and incorporated bromodeoxyuridine. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5573–5577. doi: 10.1073/pnas.80.18.5573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. EAGLE H. Amino acid metabolism in mammalian cell cultures. Science. 1959 Aug 21;130(3373):432–437. doi: 10.1126/science.130.3373.432. [DOI] [PubMed] [Google Scholar]
  6. EAGLE H. Nutrition needs of mammalian cells in tissue culture. Science. 1955 Sep 16;122(3168):501–514. doi: 10.1126/science.122.3168.501. [DOI] [PubMed] [Google Scholar]
  7. Ewen M. E., Oliver C. J., Sluss H. K., Miller S. J., Peeper D. S. p53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest. Genes Dev. 1995 Jan 15;9(2):204–217. doi: 10.1101/gad.9.2.204. [DOI] [PubMed] [Google Scholar]
  8. Ewen M. E., Sluss H. K., Sherr C. J., Matsushime H., Kato J., Livingston D. M. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993 May 7;73(3):487–497. doi: 10.1016/0092-8674(93)90136-e. [DOI] [PubMed] [Google Scholar]
  9. Guo H., Lishko V. K., Herrera H., Groce A., Kubota T., Hoffman R. M. Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res. 1993 Dec 1;53(23):5676–5679. [PubMed] [Google Scholar]
  10. HANSS J., MOORE G. E. STUDIES OF CULTURE MEDIA FOR THE GROWTH OF HUMAN TUMOR CELLS. Exp Cell Res. 1964 Apr;34:243–256. doi: 10.1016/0014-4827(64)90361-1. [DOI] [PubMed] [Google Scholar]
  11. Hester J. E., Fee W. E. Effect of arginine on growth of squamous cell carcinoma in the C3H/KM mouse. Arch Otolaryngol Head Neck Surg. 1995 Feb;121(2):193–196. doi: 10.1001/archotol.1995.01890020055011. [DOI] [PubMed] [Google Scholar]
  12. Lamb J., Wheatley D. N. Cell killing by the novel imidazoacridinone antineoplastic agent, C-1311, is inhibited at high concentrations coincident with dose-differentiated cell cycle perturbation. Br J Cancer. 1996 Nov;74(9):1359–1368. doi: 10.1038/bjc.1996.550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Neff N. T., Ross P. A., Bartholomew J. C., Bissell M. J. Leucine in cultured cells: its metabolism and use as a marker for protein turnover. Exp Cell Res. 1977 Apr;106(1):175–183. doi: 10.1016/0014-4827(77)90254-3. [DOI] [PubMed] [Google Scholar]
  14. Ormerod M. G., Orr R. M., Peacock J. H. The role of apoptosis in cell killing by cisplatin: a flow cytometric study. Br J Cancer. 1994 Jan;69(1):93–100. doi: 10.1038/bjc.1994.14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pardee A. B. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1286–1290. doi: 10.1073/pnas.71.4.1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pardee A. B. G1 events and regulation of cell proliferation. Science. 1989 Nov 3;246(4930):603–608. doi: 10.1126/science.2683075. [DOI] [PubMed] [Google Scholar]
  17. Paul D., Walter S. Growth control in primary fetal rat liver cells in culture. J Cell Physiol. 1975 Feb;85(1):113–123. doi: 10.1002/jcp.1040850112. [DOI] [PubMed] [Google Scholar]
  18. Rabinovitz M. The pleiotypic response to amino acid deprivation is the result of interactions between components of the glycolysis and protein synthesis pathways. FEBS Lett. 1992 May 11;302(2):113–116. doi: 10.1016/0014-5793(92)80418-g. [DOI] [PubMed] [Google Scholar]
  19. Rubin H., Xu K. Epigenetic features of spontaneous transformation in the NIH 3T3 line of mouse cells. Basic Life Sci. 1991;57:301–313. doi: 10.1007/978-1-4684-5994-4_25. [DOI] [PubMed] [Google Scholar]
  20. Ryan W. L., Elliott J. A. Fluorophenylalanine inhibition of tumors in mice on a phenylalanine-deficient diet. Arch Biochem Biophys. 1968 Jun;125(3):797–801. doi: 10.1016/0003-9861(68)90516-x. [DOI] [PubMed] [Google Scholar]
  21. Storr J. M., Burton A. F. The effects of arginine deficiency on lymphoma cells. Br J Cancer. 1974 Jul;30(1):50–59. doi: 10.1038/bjc.1974.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Tanaka H., Zaitsu H., Onodera K., Kimura G. Influence of the deprivation of a single amino acid on cellular proliferation and survival in rat 3Y1 fibroblasts and their derivatives transformed by a wide variety of agents. J Cell Physiol. 1988 Sep;136(3):421–430. doi: 10.1002/jcp.1041360305. [DOI] [PubMed] [Google Scholar]
  23. Tobey R. A., Ley K. D. Regulation of initiation of DNA synthesis in Chinese hamster cells. I. Production of stable, reversible G1-arrested populations in suspension culture. J Cell Biol. 1970 Jul;46(1):151–157. doi: 10.1083/jcb.46.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Warrington R. C. L-histidinol in experimental cancer chemotherapy: improving the selectivity and efficacy of anticancer drugs, eliminating metastatic disease and reversing the multidrug-resistant phenotype. Biochem Cell Biol. 1992 May;70(5):365–375. doi: 10.1139/o92-056. [DOI] [PubMed] [Google Scholar]
  25. Warrington R. C. Selective killing of oncogenic human cells cocultivated with normal human fibroblasts. J Natl Cancer Inst. 1978 Jul;61(1):69–73. doi: 10.1093/jnci/61.1.69. [DOI] [PubMed] [Google Scholar]
  26. Weissfeld A. S., Rouse H. Arginine deprivation in KB cells. I. Effect on cell cycle progress. J Cell Biol. 1977 Dec;75(3):881–888. doi: 10.1083/jcb.75.3.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Weissfeld A. S., Rouse H. Arginine deprivation in KB cells. II. Characterization of the DNA synthesized during starvation. J Cell Biol. 1977 Dec;75(3):889–898. doi: 10.1083/jcb.75.3.889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Weissfeld A. S., Rouse H. Continued initiation of DNA synthesis in arginine-deprived Chinese hamster ovary cells. J Cell Biol. 1977 Apr;73(1):200–205. doi: 10.1083/jcb.73.1.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wheatley D. N., Miseta A., Love E. M., Strickland D., Harris I. Effect of the immediate precursors of phenylalanine and tyrosine on growth and protein synthesis in phenylalanine- and tyrosine-deprived HeLa cells. Biochim Biophys Acta. 1993 Jul 10;1164(2):209–214. doi: 10.1016/0167-4838(93)90249-q. [DOI] [PubMed] [Google Scholar]
  30. Yeatman T. J., Risley G. L., Brunson M. E. Depletion of dietary arginine inhibits growth of metastatic tumor. Arch Surg. 1991 Nov;126(11):1376–1382. doi: 10.1001/archsurg.1991.01410350066010. [DOI] [PubMed] [Google Scholar]
  31. Yen A., Pardee A. B. Arrested states produced by isoleucine deprivation and their relationship to the low serum produced arrested state in Swiss 3T3 cells. Exp Cell Res. 1978 Jul;114(2):389–395. doi: 10.1016/0014-4827(78)90497-4. [DOI] [PubMed] [Google Scholar]
  32. Yin Z., Wheatley D. N. Sensitivity of 3T3 cells to low serum concentration and the associated problems of serum withdrawal. Cell Biol Int. 1994 Jan;18(1):39–46. doi: 10.1006/cbir.1994.1005. [DOI] [PubMed] [Google Scholar]

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

RESOURCES