Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;76(2):189–197. doi: 10.1038/bjc.1997.361

Retinoid metabolism and all-trans retinoic acid-induced growth inhibition in head and neck squamous cell carcinoma cell lines.

B J Braakhuis 1, I Klaassen 1, B M van der Leede 1, J Cloos 1, R H Brakenhoff 1, M P Copper 1, T Teerlink 1, H F Hendriks 1, P T van der Saag 1, G B Snow 1
PMCID: PMC2223946  PMID: 9231918

Abstract

Retinoids can reverse potentially premalignant lesions and prevent second primary tumours in patients with head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been reported that acquired resistance to all-trans retinoic acid (RA) in leukaemia is associated with decreased plasma peak levels, probably the result of enhanced retinoid metabolism. The aim of this study was to investigate the metabolism of retinoids and relate this to growth inhibition in HNSCC. Three HNSCC cell lines were selected on the basis of a large variation in the all-trans RA-induced growth inhibition. Cells were exposed to 9.5 nM (radioactive) for 4 and 24 h, and to 1 and 10 microM (nonradioactive) all-trans RA for 4, 24, 48 and 72 h, and medium and cells were analysed for retinoid metabolites. At all concentrations studied, the amount of growth inhibition was proportional to the extent at which all-trans-, 13- and 9-cis RA disappeared from the medium as well as from the cells. This turnover process coincided with the formation of a group of as yet unidentified polar retinoid metabolites. The level of mRNA of cellular RA-binding protein II (CRABP-II), involved in retinoid homeostasis, was inversely proportional to growth inhibition. These findings indicate that for HNSCC retinoid metabolism may be associated with growth inhibition.

Full text

PDF
197

Images in this article

194Figure 6
on p.194

Selected References

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

  1. Adamson P. C., Pitot H. C., Balis F. M., Rubin J., Murphy R. F., Poplack D. G. Variability in the oral bioavailability of all-trans-retinoic acid. J Natl Cancer Inst. 1993 Jun 16;85(12):993–996. doi: 10.1093/jnci/85.12.993. [DOI] [PubMed] [Google Scholar]
  2. Aström A., Tavakkol A., Pettersson U., Cromie M., Elder J. T., Voorhees J. J. Molecular cloning of two human cellular retinoic acid-binding proteins (CRABP). Retinoic acid-induced expression of CRABP-II but not CRABP-I in adult human skin in vivo and in skin fibroblasts in vitro. J Biol Chem. 1991 Sep 15;266(26):17662–17666. [PubMed] [Google Scholar]
  3. Blumberg B., Bolado J., Jr, Derguini F., Craig A. G., Moreno T. A., Chakravarti D., Heyman R. A., Buck J., Evans R. M. Novel retinoic acid receptor ligands in Xenopus embryos. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4873–4878. doi: 10.1073/pnas.93.10.4873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boylan J. F., Gudas L. J. The level of CRABP-I expression influences the amounts and types of all-trans-retinoic acid metabolites in F9 teratocarcinoma stem cells. J Biol Chem. 1992 Oct 25;267(30):21486–21491. [PubMed] [Google Scholar]
  5. Braakhuis B. J., Jansen G., Noordhuis P., Kegel A., Peters G. J. Importance of pharmacodynamics in the in vitro antiproliferative activity of the antifolates methotrexate and 10-ethyl-10-deazaaminopterin against human head and neck squamous cell carcinoma. Biochem Pharmacol. 1993 Dec 14;46(12):2155–2161. doi: 10.1016/0006-2952(93)90604-u. [DOI] [PubMed] [Google Scholar]
  6. Båvik C. O., Lévy F., Hellman U., Wernstedt C., Eriksson U. The retinal pigment epithelial membrane receptor for plasma retinol-binding protein. Isolation and cDNA cloning of the 63-kDa protein. J Biol Chem. 1993 Sep 25;268(27):20540–20546. [PubMed] [Google Scholar]
  7. Dawson M. I., Chao W. R., Pine P., Jong L., Hobbs P. D., Rudd C. K., Quick T. C., Niles R. M., Zhang X. K., Lombardo A. Correlation of retinoid binding affinity to retinoic acid receptor alpha with retinoid inhibition of growth of estrogen receptor-positive MCF-7 mammary carcinoma cells. Cancer Res. 1995 Oct 1;55(19):4446–4451. [PubMed] [Google Scholar]
  8. Delva L., Cornic M., Balitrand N., Guidez F., Micléa J. M., Delmer A., Teillet F., Fenaux P., Castaigne S., Degos L. Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells. Blood. 1993 Oct 1;82(7):2175–2181. [PubMed] [Google Scholar]
  9. Eckhoff C., Collins M. D., Nau H. Human plasma all-trans-, 13-cis- and 13-cis-4-oxoretinoic acid profiles during subchronic vitamin A supplementation: comparison to retinol and retinyl ester plasma levels. J Nutr. 1991 Jul;121(7):1016–1025. doi: 10.1093/jn/121.7.1016. [DOI] [PubMed] [Google Scholar]
  10. Eckhoff C., Nau H. Identification and quantitation of all-trans- and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma. J Lipid Res. 1990 Aug;31(8):1445–1454. [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  12. Gough N. M. Rapid and quantitative preparation of cytoplasmic RNA from small numbers of cells. Anal Biochem. 1988 Aug 15;173(1):93–95. doi: 10.1016/0003-2697(88)90164-9. [DOI] [PubMed] [Google Scholar]
  13. Griffiths C. E., Elder J. T., Bernard B. A., Rossio P., Cromie M. A., Finkel L. J., Shroot B., Voorhees J. J. Comparison of CD271 (adapalene) and all-trans retinoic acid in human skin: dissociation of epidermal effects and CRABP-II mRNA expression. J Invest Dermatol. 1993 Sep;101(3):325–328. doi: 10.1111/1523-1747.ep12365480. [DOI] [PubMed] [Google Scholar]
  14. Harding P. P., Duester G. Retinoic acid activation and thyroid hormone repression of the human alcohol dehydrogenase gene ADH3. J Biol Chem. 1992 Jul 15;267(20):14145–14150. [PubMed] [Google Scholar]
  15. Hong W. K., Endicott J., Itri L. M., Doos W., Batsakis J. G., Bell R., Fofonoff S., Byers R., Atkinson E. N., Vaughan C. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med. 1986 Dec 11;315(24):1501–1505. doi: 10.1056/NEJM198612113152401. [DOI] [PubMed] [Google Scholar]
  16. Hong W. K., Lippman S. M., Itri L. M., Karp D. D., Lee J. S., Byers R. M., Schantz S. P., Kramer A. M., Lotan R., Peters L. J. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990 Sep 20;323(12):795–801. doi: 10.1056/NEJM199009203231205. [DOI] [PubMed] [Google Scholar]
  17. Jetten A. M., Kim J. S., Sacks P. G., Rearick J. I., Lotan D., Hong W. K., Lotan R. Inhibition of growth and squamous-cell differentiation markers in cultured human head and neck squamous carcinoma cells by beta-all-trans retinoic acid. Int J Cancer. 1990 Jan 15;45(1):195–202. doi: 10.1002/ijc.2910450135. [DOI] [PubMed] [Google Scholar]
  18. Koch H. F. Biochemical treatment of precancerous oral lesions: the effectiveness of various analogues of retinoic acid. J Maxillofac Surg. 1978 Feb;6(1):59–63. doi: 10.1016/s0301-0503(78)80069-1. [DOI] [PubMed] [Google Scholar]
  19. Kurlandsky S. B., Gamble M. V., Ramakrishnan R., Blaner W. S. Plasma delivery of retinoic acid to tissues in the rat. J Biol Chem. 1995 Jul 28;270(30):17850–17857. doi: 10.1074/jbc.270.30.17850. [DOI] [PubMed] [Google Scholar]
  20. Lee J. S., Newman R. A., Lippman S. M., Huber M. H., Minor T., Raber M. N., Krakoff I. H., Hong W. K. Phase I evaluation of all-trans-retinoic acid in adults with solid tumors. J Clin Oncol. 1993 May;11(5):959–966. doi: 10.1200/JCO.1993.11.5.959. [DOI] [PubMed] [Google Scholar]
  21. Lippman S. M., Kessler J. F., Al-Sarraf M., Alberts D. S., Itri L. M., Mattox D., Von Hoff D. D., Loescher L., Meyskens F. L. Treatment of advanced squamous cell carcinoma of the head and neck with isotretinoin: a phase II randomized trial. Invest New Drugs. 1988 Apr;6(1):51–56. doi: 10.1007/BF00170781. [DOI] [PubMed] [Google Scholar]
  22. Lotan R., Xu X. C., Lippman S. M., Ro J. Y., Lee J. S., Lee J. J., Hong W. K. Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med. 1995 May 25;332(21):1405–1410. doi: 10.1056/NEJM199505253322103. [DOI] [PubMed] [Google Scholar]
  23. Martini R., Murray M. Participation of P450 3A enzymes in rat hepatic microsomal retinoic acid 4-hydroxylation. Arch Biochem Biophys. 1993 May 15;303(1):57–66. doi: 10.1006/abbi.1993.1255. [DOI] [PubMed] [Google Scholar]
  24. Muindi J. F., Scher H. I., Rigas J. R., Warrell R. P., Jr, Young C. W. Elevated plasma lipid peroxide content correlates with rapid plasma clearance of all-trans-retinoic acid in patients with advanced cancer. Cancer Res. 1994 Apr 15;54(8):2125–2128. [PubMed] [Google Scholar]
  25. Muindi J., Frankel S. R., Miller W. H., Jr, Jakubowski A., Scheinberg D. A., Young C. W., Dmitrovsky E., Warrell R. P., Jr Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia. Blood. 1992 Jan 15;79(2):299–303. [PubMed] [Google Scholar]
  26. Napoli J. L., Boerman M. H., Chai X., Zhai Y., Fiorella P. D. Enzymes and binding proteins affecting retinoic acid concentrations. J Steroid Biochem Mol Biol. 1995 Jun;53(1-6):497–502. doi: 10.1016/0960-0760(95)00096-i. [DOI] [PubMed] [Google Scholar]
  27. Pijnappel W. W., Hendriks H. F., Folkers G. E., van den Brink C. E., Dekker E. J., Edelenbosch C., van der Saag P. T., Durston A. J. The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature. 1993 Nov 25;366(6453):340–344. doi: 10.1038/366340a0. [DOI] [PubMed] [Google Scholar]
  28. Rigas J. R., Francis P. A., Muindi J. R., Kris M. G., Huselton C., DeGrazia F., Orazem J. P., Young C. W., Warrell R. P., Jr Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole. J Natl Cancer Inst. 1993 Dec 1;85(23):1921–1926. doi: 10.1093/jnci/85.23.1921. [DOI] [PubMed] [Google Scholar]
  29. Sacks P. G., Harris D., Chou T. C. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: a rationale for combination therapy with chemotherapeutic agents. Int J Cancer. 1995 May 4;61(3):409–415. doi: 10.1002/ijc.2910610322. [DOI] [PubMed] [Google Scholar]
  30. Sanquer S., Eller M. S., Gilchrest B. A. Retinoids and state of differentiation modulate CRABP II gene expression in a skin equivalent. J Invest Dermatol. 1993 Feb;100(2):148–153. doi: 10.1111/1523-1747.ep12462785. [DOI] [PubMed] [Google Scholar]
  31. Stich H. F., Hornby A. P., Mathew B., Sankaranarayanan R., Nair M. K. Response of oral leukoplakias to the administration of vitamin A. Cancer Lett. 1988 May;40(1):93–101. doi: 10.1016/0304-3835(88)90266-2. [DOI] [PubMed] [Google Scholar]
  32. Takatsuka J., Takahashi N., de Luca L. M. Retinoic acid metabolism and inhibition of cell proliferation: an unexpected liaison. Cancer Res. 1996 Feb 15;56(4):675–678. [PubMed] [Google Scholar]
  33. Wouters W., van Dun J., Dillen A., Coene M. C., Cools W., De Coster R. Effects of liarozole, a new antitumoral compound, on retinoic acid-induced inhibition of cell growth and on retinoic acid metabolism in MCF-7 human breast cancer cells. Cancer Res. 1992 May 15;52(10):2841–2846. [PubMed] [Google Scholar]
  34. Xu X. C., Ro J. Y., Lee J. S., Shin D. M., Hong W. K., Lotan R. Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues. Cancer Res. 1994 Jul 1;54(13):3580–3587. [PubMed] [Google Scholar]
  35. Zou C. P., Clifford J. L., Xu X. C., Sacks P. G., Chambon P., Hong W. K., Lotan R. Modulation by retinoic acid (RA) of squamous cell differentiation, cellular RA-binding proteins, and nuclear RA receptors in human head and neck squamous cell carcinoma cell lines. Cancer Res. 1994 Oct 15;54(20):5479–5487. [PubMed] [Google Scholar]

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

RESOURCES