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. 1987 Apr;84(8):2208–2212. doi: 10.1073/pnas.84.8.2208

Induction of differentiation of human promyelocytic leukemia cell line HL-60 by retinoyl glucuronide, a biologically active metabolite of vitamin A.

M H Zile, M E Cullum, R U Simpson, A B Barua, D A Swartz
PMCID: PMC304618  PMID: 3470785

Abstract

We examined the differentiation activity of retinoyl beta-D-glucuronide, a biologically active physiological metabolite of vitamin A, using the human promyelocytic leukemic cell line HL-60, which can be induced to differentiate with retinoic acid. Retinoyl beta-D-glucuronide (1 microM) inhibited HL-60 cell proliferation by 55-75%, inhibited tritiated thymidine incorporation into DNA by 63-80%, and induced 38-50% of the cells to differentiate into mature granulocytes. The potency of growth inhibition and induction of differentiation by retinoyl beta-D-glucuronide was similar to that of all-trans-retinoic acid. The continuous presence of either retinoyl beta-D-glucuronide or all-trans-retinoic acid was not required to obtain maximum growth arrest and differentiation: a 1-hr exposure of HL-60 cells to the retinoids gave the same response (measured after a total incubation time of 48 hr) as a 24-hr or 48-hr continuous treatment. Retinoyl beta-D-glucuronide (0.1-0.2 mM) was 50% less cytotoxic to HL-60 cells than all-trans-retinoic acid at an equimolar concentration. Retinoyl beta-D-glucuronide was not significantly metabolized to other retinoids; retinoic acid was not formed during incubation. We conclude that retinoyl beta-D-glucuronide can arrest HL-60 cell proliferation and induce their differentiation into mature granulocytes; it may act by itself or by being hydrolyzed to retinoic acid, which could be immediately utilized and metabolized. The therapeutic use of this retinoid as an antineoplastic agent is suggested.

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Selected References

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  1. Barua A. B., Olson J. A. Chemical synthesis of all-trans retinoyl beta-glucuronide. J Lipid Res. 1985 Oct;26(10):1277–1282. [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  3. Breitman T. R., Collins S. J., Keene B. R. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood. 1981 Jun;57(6):1000–1004. [PubMed] [Google Scholar]
  4. Breitman T. R., Selonick S. E., Collins S. J. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci U S A. 1980 May;77(5):2936–2940. doi: 10.1073/pnas.77.5.2936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Collins S. J., Gallo R. C., Gallagher R. E. Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture. Nature. 1977 Nov 24;270(5635):347–349. doi: 10.1038/270347a0. [DOI] [PubMed] [Google Scholar]
  6. Collins S. J., Ruscetti F. W., Gallagher R. E., Gallo R. C. Normal functional characteristics of cultured human promyelocytic leukemia cells (HL-60) after induction of differentiation by dimethylsulfoxide. J Exp Med. 1979 Apr 1;149(4):969–974. doi: 10.1084/jem.149.4.969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cullum M. E., Zile M. H. Metabolism of all-trans-retinoic acid and all-trans-retinyl acetate. Demonstration of common physiological metabolites in rat small intestinal mucosa and circulation. J Biol Chem. 1985 Sep 5;260(19):10590–10596. [PubMed] [Google Scholar]
  8. Cullum M. E., Zile M. H. Quantitation of biological retinoids by high-pressure liquid chromatography: primary internal standardization using tritiated retinoids. Anal Biochem. 1986 Feb 15;153(1):23–32. doi: 10.1016/0003-2697(86)90055-2. [DOI] [PubMed] [Google Scholar]
  9. Daenen S., Vellenga E., van Dobbenburgh O. A., Halie M. R. Retinoic acid as antileukemic therapy in a patient with acute promyelocytic leukemia and Aspergillus pneumonia. Blood. 1986 Feb;67(2):559–561. [PubMed] [Google Scholar]
  10. Douer D., Koeffler H. P. Retinoic acid. Inhibition of the clonal growth of human myeloid leukemia cells. J Clin Invest. 1982 Feb;69(2):277–283. doi: 10.1172/JCI110450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fontana J. A., Rogers J. S., 2nd, Durham J. P. The role of 13 cis-retinoic acid in the remission induction of a patient with acute promyelocytic leukemia. Cancer. 1986 Jan 15;57(2):209–217. doi: 10.1002/1097-0142(19860115)57:2<209::aid-cncr2820570204>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  12. Koeffler H. P., Amatruda T. T., 3rd The effect of retinoids on haemopoiesis--clinical and laboratory studies. Ciba Found Symp. 1985;113:252–267. doi: 10.1002/9780470720943.ch14. [DOI] [PubMed] [Google Scholar]
  13. Koeffler H. P. Induction of differentiation of human acute myelogenous leukemia cells: therapeutic implications. Blood. 1983 Oct;62(4):709–721. [PubMed] [Google Scholar]
  14. LEVVY G. A. The preparation and properties of beta-glucuronidase. IV. Inhibition by sugar acids and their lactones. Biochem J. 1952 Nov;52(3):464–472. doi: 10.1042/bj0520464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lippel K., Olson J. A. Origin of some derivatives of retinoic acid found in rat bile. J Lipid Res. 1968 Sep;9(5):580–586. [PubMed] [Google Scholar]
  16. Lotan R. Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochim Biophys Acta. 1980 Mar 12;605(1):33–91. doi: 10.1016/0304-419x(80)90021-9. [DOI] [PubMed] [Google Scholar]
  17. Mahrle G. Retinoids in oncology. Curr Probl Dermatol. 1985;13:128–163. [PubMed] [Google Scholar]
  18. Meyskens F. L., Jr, Goodman G. E., Alberts D. S. 13-Cis-retinoic acid: pharmacology, toxicology, and clinical applications for the prevention and treatment of human cancer. Crit Rev Oncol Hematol. 1985;3(1):75–101. doi: 10.1016/s1040-8428(85)80040-8. [DOI] [PubMed] [Google Scholar]
  19. Murtaugh M. P., Dennison O., Stein J. P., Davies P. J. Retinoic acid-induced gene expression in normal and leukemic myeloid cells. J Exp Med. 1986 May 1;163(5):1325–1330. doi: 10.1084/jem.163.5.1325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sietsema W. K., DeLuca H. F. A new vaginal smear assay for vitamin A in rats. J Nutr. 1982 Aug;112(8):1481–1489. doi: 10.1093/jn/112.8.1481. [DOI] [PubMed] [Google Scholar]
  21. Stephens-Jarnagin A., Sietsema W. K., Miller D. A., DeLuca H. F. The biological activity of rat intestinal retinoic acid metabolites in the vaginal smear assay. Arch Biochem Biophys. 1983 Feb 1;220(2):502–508. doi: 10.1016/0003-9861(83)90441-1. [DOI] [PubMed] [Google Scholar]
  22. Strickland S., Breitman T. R., Frickel F., Nürrenbach A., Hädicke E., Sporn M. B. Structure-activity relationships of a new series of retinoidal benzoic acid derivatives as measured by induction of differentiation of murine F9 teratocarcinoma cells and human HL-60 promyelocytic leukemia cells. Cancer Res. 1983 Nov;43(11):5268–5272. [PubMed] [Google Scholar]
  23. Thomas G. A., Simpson R. U. High performance liquid chromatography analysis of 1,25-dihydroxyvitamin D3 receptor in malignant cells. Correlation of effects on cell proliferation and receptor concentration. Cancer Biochem Biophys. 1986 Jul;8(3):221–234. [PubMed] [Google Scholar]
  24. Vahlquist A. Clinical use of vitamin A and its derivatives--physiological and pharmacological aspects. Clin Exp Dermatol. 1985 Mar;10(2):133–143. doi: 10.1111/j.1365-2230.1985.tb00541.x. [DOI] [PubMed] [Google Scholar]
  25. Wolf G. Multiple functions of vitamin A. Physiol Rev. 1984 Jul;64(3):873–937. doi: 10.1152/physrev.1984.64.3.873. [DOI] [PubMed] [Google Scholar]
  26. Yen A., Powers V., Fishbaugh J. Retinoic acid induced HL-60 myeloid differentiation: dependence of early and late events on isomeric structure. Leuk Res. 1986;10(6):619–629. doi: 10.1016/0145-2126(86)90264-x. [DOI] [PubMed] [Google Scholar]
  27. Zile M. H., Inhorn R. C., DeLuca H. F. Metabolism in vivo of all-trans-retinoic acid. Biosynthesis of 13-cis-retinoic acid and all-trans- and 13-cis-retinoyl glucuronides in the intestinal mucosa of the rat. J Biol Chem. 1982 Apr 10;257(7):3544–3550. [PubMed] [Google Scholar]

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