Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Sep 24;79(1):101–107. doi: 10.1038/sj.bjc.6690018

Synergistic inhibition of prostate cancer cell lines by a 19- nor hexafluoride vitamin D3 analogue and anti-activator protein 1 retinoid

M J Campbell 1, S Park 1, M R Uskokovic 2, M I Dawson 3, L Jong 3, H P Koeffler 1
PMCID: PMC2362165  PMID: 10408700

Abstract

The secosteroid hormones, all- trans- and 9- cis -retinoic acid and vitamin D3, have demonstrated significant capacity to control proliferation in itro of many solid tumour cell lines. Cooperative synergistic effects by these two ligands have been reported, and it is, therefore, possible that greater therapeutic effects could be achieved if these compounds were administered together. The role of retinoid-dependent anti-activator protein 1 (anti-AP-1) effects in controlling cancer cell proliferation appears significant. We have utilized an anti- AP-1 retinoid [2-(4,4-dimethyl-3,4-dihydro-2H-1 benzopyran-6-yl)carbonyl-2-(4-carboxyphenyl)-1,3,-dithiane; SR11238], which does not transactivate through a retinoic acid response element (RARE), and a potent vitamin D3analogue [1α,25(OH)2-16-ene-23-yne-26,27-F6-19-nor -D3, code name LH] together at low, physiologically safer doses against a panel of prostate cancer cell lines that represent progressively more transformed phenotypes. The LNCaP (least transformed) and PC-3 (intermediately transformed) cell lines were synergistically inhibited in their clonal growth by the combination of LH and SR11238, whereas SR11238 alone was essentially inactive. DU-145 cells (most transformed) were completely insensitive to these analogues. LNCaP cells, but neither PC-3 nor DU-145, underwent apoptosis in the presence of LH and SR11238. Transactivation of the human osteocalcin vitamin D response element (VDRE) by LH was not enhanced in the presence of SR11238, although the expression of E-cadherin in these cells was additively up-regulated in the presence of both compounds. These data suggest the anti-AP-1 retinoid and the vitamin D3 analogue may naturally act synergistically to control cell proliferation, a process that is interrupted during transformation, and that this combination may form the basis for treatment of some androgen-independent prostate cancer. © 1999 Cancer Research Campaign

Keywords: vitamin D3, retinoids, activator protein 1, growth inhibition, prostate cancer

Full Text

The Full Text of this article is available as a PDF (74.8 KB).

Selected References

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

  1. Alroy I., Towers T. L., Freedman L. P. Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol. 1995 Oct;15(10):5789–5799. doi: 10.1128/mcb.15.10.5789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blutt S. E., Allegretto E. A., Pike J. W., Weigel N. L. 1,25-dihydroxyvitamin D3 and 9-cis-retinoic acid act synergistically to inhibit the growth of LNCaP prostate cells and cause accumulation of cells in G1. Endocrinology. 1997 Apr;138(4):1491–1497. doi: 10.1210/endo.138.4.5063. [DOI] [PubMed] [Google Scholar]
  3. Bollag W. Experimental basis of cancer combination chemotherapy with retinoids, cytokines, 1,25-dihydroxyvitamin D3, and analogs. J Cell Biochem. 1994 Dec;56(4):427–435. doi: 10.1002/jcb.240560402. [DOI] [PubMed] [Google Scholar]
  4. Brown G., Bunce C. M., Rowlands D. C., Williams G. R. All-trans retinoic acid and 1 alpha,25-dihydroxyvitamin D3 co-operate to promote differentiation of the human promyeloid leukemia cell line HL60 to monocytes. Leukemia. 1994 May;8(5):806–815. [PubMed] [Google Scholar]
  5. Campbell M. J., Dawson M., Koeffler H. P. Growth inhibition of DU-145 prostate cancer cells by a Bcl-2 antisense oligonucleotide is enhanced by N-(2-hydroxyphenyl)all-trans retinamide. Br J Cancer. 1998 Mar;77(5):739–744. doi: 10.1038/bjc.1998.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Campbell M. J., Elstner E., Holden S., Uskokovic M., Koeffler H. P. Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. J Mol Endocrinol. 1997 Aug;19(1):15–27. doi: 10.1677/jme.0.0190015. [DOI] [PubMed] [Google Scholar]
  7. Campbell M. J., Park S., Uskokovic M. R., Dawson M. I., Koeffler H. P. Expression of retinoic acid receptor-beta sensitizes prostate cancer cells to growth inhibition mediated by combinations of retinoids and a 19-nor hexafluoride vitamin D3 analog. Endocrinology. 1998 Apr;139(4):1972–1980. doi: 10.1210/endo.139.4.5943. [DOI] [PubMed] [Google Scholar]
  8. Campbell M. J., Reddy G. S., Koeffler H. P. Vitamin D3 analogs and their 24-oxo metabolites equally inhibit clonal proliferation of a variety of cancer cells but have differing molecular effects. J Cell Biochem. 1997 Sep 1;66(3):413–425. [PubMed] [Google Scholar]
  9. Carroll A. G., Voeller H. J., Sugars L., Gelmann E. P. p53 oncogene mutations in three human prostate cancer cell lines. Prostate. 1993;23(2):123–134. doi: 10.1002/pros.2990230206. [DOI] [PubMed] [Google Scholar]
  10. Chen J. Y., Penco S., Ostrowski J., Balaguer P., Pons M., Starrett J. E., Reczek P., Chambon P., Gronemeyer H. RAR-specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage-independent cell proliferation. EMBO J. 1995 Mar 15;14(6):1187–1197. doi: 10.1002/j.1460-2075.1995.tb07102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cheng L., Nagabhushan M., Pretlow T. P., Amini S. B., Pretlow T. G. Expression of E-cadherin in primary and metastatic prostate cancer. Am J Pathol. 1996 May;148(5):1375–1380. [PMC free article] [PubMed] [Google Scholar]
  12. Danesi R., Figg W. D., Reed E., Myers C. E. Paclitaxel (taxol) inhibits protein isoprenylation and induces apoptosis in PC-3 human prostate cancer cells. Mol Pharmacol. 1995 Jun;47(6):1106–1111. [PubMed] [Google Scholar]
  13. Elstner E., Linker-Israeli M., Umiel T., Le J., Grillier I., Said J., Shintaku I. P., Krajewski S., Reed J. C., Binderup L. Combination of a potent 20-epi-vitamin D3 analogue (KH 1060) with 9-cis-retinoic acid irreversibly inhibits clonal growth, decreases bcl-2 expression, and induces apoptosis in HL-60 leukemic cells. Cancer Res. 1996 Aug 1;56(15):3570–3576. [PubMed] [Google Scholar]
  14. Ewing C. M., Ru N., Morton R. A., Robinson J. C., Wheelock M. J., Johnson K. R., Barrett J. C., Isaacs W. B. Chromosome 5 suppresses tumorigenicity of PC3 prostate cancer cells: correlation with re-expression of alpha-catenin and restoration of E-cadherin function. Cancer Res. 1995 Nov 1;55(21):4813–4817. [PubMed] [Google Scholar]
  15. Fanjul A., Dawson M. I., Hobbs P. D., Jong L., Cameron J. F., Harlev E., Graupner G., Lu X. P., Pfahl M. A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature. 1994 Nov 3;372(6501):107–111. doi: 10.1038/372107a0. [DOI] [PubMed] [Google Scholar]
  16. Feldman D., Skowronski R. J., Peehl D. M. Vitamin D and prostate cancer. Adv Exp Med Biol. 1995;375:53–63. doi: 10.1007/978-1-4899-0949-7_5. [DOI] [PubMed] [Google Scholar]
  17. Feldman D., Skowronski R. J., Peehl D. M. Vitamin D and prostate cancer. Adv Exp Med Biol. 1995;375:53–63. doi: 10.1007/978-1-4899-0949-7_5. [DOI] [PubMed] [Google Scholar]
  18. Gaddipati J. P., McLeod D. G., Heidenberg H. B., Sesterhenn I. A., Finger M. J., Moul J. W., Srivastava S. Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. Cancer Res. 1994 Jun 1;54(11):2861–2864. [PubMed] [Google Scholar]
  19. Hengst L., Reed S. I. Translational control of p27Kip1 accumulation during the cell cycle. Science. 1996 Mar 29;271(5257):1861–1864. doi: 10.1126/science.271.5257.1861. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Hsieh T. C., Xu W., Chiao J. W. Growth regulation and cellular changes during differentiation of human prostatic cancer LNCaP cells as induced by T lymphocyte-conditioned medium. Exp Cell Res. 1995 May;218(1):137–143. doi: 10.1006/excr.1995.1140. [DOI] [PubMed] [Google Scholar]
  22. Huang M. E., Ye Y. C., Chen S. R., Chai J. R., Lu J. X., Zhoa L., Gu L. J., Wang Z. Y. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988 Aug;72(2):567–572. [PubMed] [Google Scholar]
  23. Isaacs W. B., Bova G. S., Morton R. A., Bussemakers M. J., Brooks J. D., Ewing C. M. Genetic alterations in prostate cancer. Cold Spring Harb Symp Quant Biol. 1994;59:653–659. doi: 10.1101/sqb.1994.059.01.075. [DOI] [PubMed] [Google Scholar]
  24. Jäskeläinen T., Pirskanen A., Ryhänen S., Palvimo J. J., Deluca H. F., Mäenpä P. H. Functional interference between AP-1 and the vitamin D receptor on osteocalcin gene expression in human osteosarcoma cells. Eur J Biochem. 1994 Aug 15;224(1):11–20. doi: 10.1111/j.1432-1033.1994.tb19989.x. [DOI] [PubMed] [Google Scholar]
  25. Kantarjian H. M., Estey E. H., Keating M. A. New chemotherapeutic agents in acute myeloid leukemia. Leukemia. 1996 Apr;10 (Suppl 1):S4–S6. [PubMed] [Google Scholar]
  26. Konety B. R., Schwartz G. G., Acierno J. S., Jr, Becich M. J., Getzenberg R. H. The role of vitamin D in normal prostate growth and differentiation. Cell Growth Differ. 1996 Nov;7(11):1563–1570. [PubMed] [Google Scholar]
  27. Li C. J., Wang C., Pardee A. B. Induction of apoptosis by beta-lapachone in human prostate cancer cells. Cancer Res. 1995 Sep 1;55(17):3712–3715. [PubMed] [Google Scholar]
  28. Li J. J., Dong Z., Dawson M. I., Colburn N. H. Inhibition of tumor promoter-induced transformation by retinoids that transrepress AP-1 without transactivating retinoic acid response element. Cancer Res. 1996 Feb 1;56(3):483–489. [PubMed] [Google Scholar]
  29. Li X. S., Rishi A. K., Shao Z. M., Dawson M. I., Jong L., Shroot B., Reichert U., Ordonez J., Fontana J. A. Posttranscriptional regulation of p21WAF1/CIP1 expression in human breast carcinoma cells. Cancer Res. 1996 Nov 1;56(21):5055–5062. [PubMed] [Google Scholar]
  30. Li X., Darzynkiewicz Z. Labelling DNA strand breaks with BrdUTP. Detection of apoptosis and cell proliferation. Cell Prolif. 1995 Nov;28(11):571–579. doi: 10.1111/j.1365-2184.1995.tb00045.x. [DOI] [PubMed] [Google Scholar]
  31. Liu L., Shack S., Stetler-Stevenson W. G., Hudgins W. R., Samid D. Differentiation of cultured human melanoma cells induced by the aromatic fatty acids phenylacetate and phenylbutyrate. J Invest Dermatol. 1994 Sep;103(3):335–340. doi: 10.1111/1523-1747.ep12394874. [DOI] [PubMed] [Google Scholar]
  32. Liu M., Iavarone A., Freedman L. P. Transcriptional activation of the human p21(WAF1/CIP1) gene by retinoic acid receptor. Correlation with retinoid induction of U937 cell differentiation. J Biol Chem. 1996 Dec 6;271(49):31723–31728. doi: 10.1074/jbc.271.49.31723. [DOI] [PubMed] [Google Scholar]
  33. Liu M., Lee M. H., Cohen M., Bommakanti M., Freedman L. P. Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev. 1996 Jan 15;10(2):142–153. doi: 10.1101/gad.10.2.142. [DOI] [PubMed] [Google Scholar]
  34. Liu W., Hillmann A. G., Harmon J. M. Hormone-independent repression of AP-1-inducible collagenase promoter activity by glucocorticoid receptors. Mol Cell Biol. 1995 Feb;15(2):1005–1013. doi: 10.1128/mcb.15.2.1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mangelsdorf D. J., Thummel C., Beato M., Herrlich P., Schütz G., Umesono K., Blumberg B., Kastner P., Mark M., Chambon P. The nuclear receptor superfamily: the second decade. Cell. 1995 Dec 15;83(6):835–839. doi: 10.1016/0092-8674(95)90199-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Morosetti R., Koeffler H. P. Differentiation therapy in myelodysplastic syndromes. Semin Hematol. 1996 Jul;33(3):236–245. [PubMed] [Google Scholar]
  37. Munker R., Kobayashi T., Elstner E., Norman A. W., Uskokovic M., Zhang W., Andreeff M., Koeffler H. P. A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia. Blood. 1996 Sep 15;88(6):2201–2209. [PubMed] [Google Scholar]
  38. Munker R., Norman A., Koeffler H. P. Vitamin D compounds. Effect on clonal proliferation and differentiation of human myeloid cells. J Clin Invest. 1986 Aug;78(2):424–430. doi: 10.1172/JCI112593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Norman A. W., Zhou J. Y., Henry H. L., Uskokovic M. R., Koeffler H. P. Structure-function studies on analogues of 1 alpha,25-dihydroxyvitamin D3: differential effects on leukemic cell growth, differentiation, and intestinal calcium absorption. Cancer Res. 1990 Nov 1;50(21):6857–6864. [PubMed] [Google Scholar]
  40. Novichenko N., Konno S., Nakajima Y., Hsieh T. C., Xu W., Turo K., Ahmed T., Chiao J. W. Growth attenuation in a human prostate cell line mediated by a phorbol ester. Proc Soc Exp Biol Med. 1995 Jun;209(2):152–156. doi: 10.3181/00379727-209-43889. [DOI] [PubMed] [Google Scholar]
  41. Otto T., Rembrink K., Goepel M., Meyer-Schwickerath M., Rübben H. E-cadherin: a marker for differentiation and invasiveness in prostatic carcinoma. Urol Res. 1993;21(5):359–362. doi: 10.1007/BF00296837. [DOI] [PubMed] [Google Scholar]
  42. Pakkala S., de Vos S., Elstner E., Rude R. K., Uskokovic M., Binderup L., Koeffler H. P. Vitamin D3 analogs: effect on leukemic clonal growth and differentiation, and on serum calcium levels. Leuk Res. 1995 Jan;19(1):65–72. doi: 10.1016/0145-2126(94)00065-i. [DOI] [PubMed] [Google Scholar]
  43. Parker S. L., Tong T., Bolden S., Wingo P. A. Cancer statistics, 1997. CA Cancer J Clin. 1997 Jan-Feb;47(1):5–27. doi: 10.3322/canjclin.47.1.5. [DOI] [PubMed] [Google Scholar]
  44. Peehl D. M., Skowronski R. J., Leung G. K., Wong S. T., Stamey T. A., Feldman D. Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res. 1994 Feb 1;54(3):805–810. [PubMed] [Google Scholar]
  45. Perez P., Schönthal A., Aranda A. Repression of c-fos gene expression by thyroid hormone and retinoic acid receptors. J Biol Chem. 1993 Nov 5;268(31):23538–23543. [PubMed] [Google Scholar]
  46. Planchon S. M., Wuerzberger S., Frydman B., Witiak D. T., Hutson P., Church D. R., Wilding G., Boothman D. A. Beta-lapachone-mediated apoptosis in human promyelocytic leukemia (HL-60) and human prostate cancer cells: a p53-independent response. Cancer Res. 1995 Sep 1;55(17):3706–3711. [PMC free article] [PubMed] [Google Scholar]
  47. Rosenauer A., Raelson J. V., Nervi C., Eydoux P., DeBlasio A., Miller W. H., Jr Alterations in expression, binding to ligand and DNA, and transcriptional activity of rearranged and wild-type retinoid receptors in retinoid-resistant acute promyelocytic leukemia cell lines. Blood. 1996 Oct 1;88(7):2671–2682. [PubMed] [Google Scholar]
  48. Rosenthal N. Identification of regulatory elements of cloned genes with functional assays. Methods Enzymol. 1987;152:704–720. doi: 10.1016/0076-6879(87)52075-4. [DOI] [PubMed] [Google Scholar]
  49. Salbert G., Fanjul A., Piedrafita F. J., Lu X. P., Kim S. J., Tran P., Pfahl M. Retinoic acid receptors and retinoid X receptor-alpha down-regulate the transforming growth factor-beta 1 promoter by antagonizing AP-1 activity. Mol Endocrinol. 1993 Oct;7(10):1347–1356. doi: 10.1210/mend.7.10.8264664. [DOI] [PubMed] [Google Scholar]
  50. Samid D., Shack S., Myers C. E. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate. J Clin Invest. 1993 May;91(5):2288–2295. doi: 10.1172/JCI116457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Saunders D. E., Christensen C., Williams J. R., Wappler N. L., Lawrence W. D., Malone J. M., Malviya V. K., Deppe G. Inhibition of breast and ovarian carcinoma cell growth by 1,25-dihydroxyvitamin D3 combined with retinoic acid or dexamethasone. Anticancer Drugs. 1995 Aug;6(4):562–569. doi: 10.1097/00001813-199508000-00009. [DOI] [PubMed] [Google Scholar]
  52. Schwaller J., Koeffler H. P., Niklaus G., Loetscher P., Nagel S., Fey M. F., Tobler A. Posttranscriptional stabilization underlies p53-independent induction of p21WAF1/CIP1/SDI1 in differentiating human leukemic cells. J Clin Invest. 1995 Mar;95(3):973–979. doi: 10.1172/JCI117806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Simonson M. S. Anti-AP-1 activity of all-trans retinoic acid in glomerular mesangial cells. Am J Physiol. 1994 Nov;267(5 Pt 2):F805–F815. doi: 10.1152/ajprenal.1994.267.5.F805. [DOI] [PubMed] [Google Scholar]
  54. Tamimi Y., Bringuier P. P., Smit F., van Bokhoven A., Debruyne F. M., Schalken J. A. p16 mutations/deletions are not frequent events in prostate cancer. Br J Cancer. 1996 Jul;74(1):120–122. doi: 10.1038/bjc.1996.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Umbas R., Isaacs W. B., Bringuier P. P., Schaafsma H. E., Karthaus H. F., Oosterhof G. O., Debruyne F. M., Schalken J. A. Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res. 1994 Jul 15;54(14):3929–3933. [PubMed] [Google Scholar]
  56. Umbas R., Schalken J. A., Aalders T. W., Carter B. S., Karthaus H. F., Schaafsma H. E., Debruyne F. M., Isaacs W. B. Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res. 1992 Sep 15;52(18):5104–5109. [PubMed] [Google Scholar]
  57. Wang Q. M., Jones J. B., Studzinski G. P. Cyclin-dependent kinase inhibitor p27 as a mediator of the G1-S phase block induced by 1,25-dihydroxyvitamin D3 in HL60 cells. Cancer Res. 1996 Jan 15;56(2):264–267. [PubMed] [Google Scholar]
  58. Welsh J. Induction of apoptosis in breast cancer cells in response to vitamin D and antiestrogens. Biochem Cell Biol. 1994 Nov-Dec;72(11-12):537–545. doi: 10.1139/o94-072. [DOI] [PubMed] [Google Scholar]
  59. Zhang W., Grasso L., McClain C. D., Gambel A. M., Cha Y., Travali S., Deisseroth A. B., Mercer W. E. p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. Cancer Res. 1995 Feb 1;55(3):668–674. [PubMed] [Google Scholar]
  60. de Grazia U., Felli M. P., Vacca A., Farina A. R., Maroder M., Cappabianca L., Meco D., Farina M., Screpanti I., Frati L. Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, Oct-2, and retinoic acid receptor. J Exp Med. 1994 Oct 1;180(4):1485–1497. doi: 10.1084/jem.180.4.1485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. van der Burg B., Slager-Davidov R., van der Leede B. M., de Laat S. W., van der Saag P. T. Differential regulation of AP1 activity by retinoic acid in hormone-dependent and -independent breast cancer cells. Mol Cell Endocrinol. 1995 Aug 11;112(2):143–152. doi: 10.1016/0303-7207(95)03600-c. [DOI] [PubMed] [Google Scholar]

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

RESOURCES