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. 2001 Jun;84(11):1571–1576. doi: 10.1054/bjoc.2001.1818

Modulation of docetaxel-induced apoptosis and cell cycle arrest by all- trans retinoic acid in prostate cancer cells

A Nehmé 1, P Varadarajan 1, G Sellakumar 1, M Gerhold 1, H Niedner 1, Q Zhang 1, X Lin 1, R D Christen 1
PMCID: PMC2363662  PMID: 11384110

Abstract

We report that all- trans retinoic acid (ATRA) enhanced the toxicity of docetaxel against DU145 and LNCaP prostate cancer cells, and that the nature of the interaction between ATRA and docetaxel was highly synergistic. Docetaxel-induced apoptotic cell death was associated with phosphorylation and hence inactivation of Bcl-2. ATRA enhanced docetaxel-induced apoptosis and combined treatment with ATRA and docetaxel resulted in down-regulation of Bcl-2. Docetaxel caused phosphorylation and hence inactivation of cdc2 kinase result ing in G2/M arrest. ATRA inhibited docetaxel-induced phosphorylation of cdc2 resulting in activation of cdc2 kinase and partial reversal of the G2/M arrest. ATRA also inhibited docetaxel-induced activation of MAPK indicating that the effects of docetaxel and ATRA on cdc2 phosphorylation are dependent on MAPK. We conclude that ATRA synergistically enhances docetaxel toxicity by down-regulating Bcl-2 expression and partially reverses the docetaxel-induced G2/M arrest by inhibiting docetaxel-induced cdc2 phosphorylation in a pathway that is dependent on MAPK. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: docetaxel, all- trans retinoic acid, prostate cancer, apoptosis, cell cycle

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Selected References

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  1. Aebi S., Kröning R., Cenni B., Sharma A., Fink D., Los G., Weisman R., Howell S. B., Christen R. D. all-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian adenocarcinoma and in squamous head and neck cancer cells. Clin Cancer Res. 1997 Nov;3(11):2033–2038. [PubMed] [Google Scholar]
  2. Amos B., Lotan R. Retinoid-sensitive cells and cell lines. Methods Enzymol. 1990;190:217–225. doi: 10.1016/0076-6879(90)90026-w. [DOI] [PubMed] [Google Scholar]
  3. Andreeff M., Jiang S., Zhang X., Konopleva M., Estrov Z., Snell V. E., Xie Z., Okcu M. F., Sanchez-Williams G., Dong J. Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. Leukemia. 1999 Nov;13(11):1881–1892. doi: 10.1038/sj.leu.2401573. [DOI] [PubMed] [Google Scholar]
  4. Bitangcol J. C., Chau A. S., Stadnick E., Lohka M. J., Dicken B., Shibuya E. K. Activation of the p42 mitogen-activated protein kinase pathway inhibits Cdc2 activation and entry into M-phase in cycling Xenopus egg extracts. Mol Biol Cell. 1998 Feb;9(2):451–467. doi: 10.1091/mbc.9.2.451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bradbury D. A., Aldington S., Zhu Y. M., Russell N. H. Down-regulation of bcl-2 in AML blasts by all-trans retinoic acid and its relationship to CD34 antigen expression. Br J Haematol. 1996 Sep;94(4):671–675. doi: 10.1046/j.1365-2141.1996.d01-1838.x. [DOI] [PubMed] [Google Scholar]
  6. Caliaro M. J., Marmouget C., Guichard S., Mazars P., Valette A., Moisand A., Bugat R., Jozan S. Response of four human ovarian carcinoma cell lines to all-trans retinoic acid: relationship with induction of differentiation and retinoic acid receptor expression. Int J Cancer. 1994 Mar 1;56(5):743–748. doi: 10.1002/ijc.2910560522. [DOI] [PubMed] [Google Scholar]
  7. Caliaro M. J., Vitaux P., Lafon C., Lochon I., Néhmé A., Valette A., Canal P., Bugat R., Jozan S. Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines. Br J Cancer. 1997;75(3):333–340. doi: 10.1038/bjc.1997.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Catalona W. J. Management of cancer of the prostate. N Engl J Med. 1994 Oct 13;331(15):996–1004. doi: 10.1056/NEJM199410133311507. [DOI] [PubMed] [Google Scholar]
  9. Chou T. C., Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55. doi: 10.1016/0065-2571(84)90007-4. [DOI] [PubMed] [Google Scholar]
  10. Dean P. N., Jett J. H. Mathematical analysis of DNA distributions derived from flow microfluorometry. J Cell Biol. 1974 Feb;60(2):523–527. doi: 10.1083/jcb.60.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ding A., Chen B., Fuortes M., Blum E. Association of mitogen-activated protein kinases with microtubules in mouse macrophages. J Exp Med. 1996 Apr 1;183(4):1899–1904. doi: 10.1084/jem.183.4.1899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Formelli F., Cleris L. Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity. Cancer Res. 1993 Nov 15;53(22):5374–5376. [PubMed] [Google Scholar]
  13. Haldar S., Basu A., Croce C. M. Bcl2 is the guardian of microtubule integrity. Cancer Res. 1997 Jan 15;57(2):229–233. [PubMed] [Google Scholar]
  14. Haldar S., Basu A., Croce C. M. Serine-70 is one of the critical sites for drug-induced Bcl2 phosphorylation in cancer cells. Cancer Res. 1998 Apr 15;58(8):1609–1615. [PubMed] [Google Scholar]
  15. Haldar S., Chintapalli J., Croce C. M. Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res. 1996 Mar 15;56(6):1253–1255. [PubMed] [Google Scholar]
  16. Haldar S., Jena N., Croce C. M. Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4507–4511. doi: 10.1073/pnas.92.10.4507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Haldar S., Negrini M., Monne M., Sabbioni S., Croce C. M. Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 1994 Apr 15;54(8):2095–2097. [PubMed] [Google Scholar]
  18. Hu Z. B., Minden M. D., McCulloch E. A. Direct evidence for the participation of bcl-2 in the regulation by retinoic acid of the Ara-C sensitivity of leukemic stem cells. Leukemia. 1995 Oct;9(10):1667–1673. [PubMed] [Google Scholar]
  19. Hu Z. B., Minden M. D., McCulloch E. A. Phosphorylation of BCL-2 after exposure of human leukemic cells to retinoic acid. Blood. 1998 Sep 1;92(5):1768–1775. [PubMed] [Google Scholar]
  20. Kaufmann S. H., Desnoyers S., Ottaviano Y., Davidson N. E., Poirier G. G. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res. 1993 Sep 1;53(17):3976–3985. [PubMed] [Google Scholar]
  21. Lin A., Minden A., Martinetto H., Claret F. X., Lange-Carter C., Mercurio F., Johnson G. L., Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. doi: 10.1126/science.7716521. [DOI] [PubMed] [Google Scholar]
  22. Lotan R. Suppression of squamous cell carcinoma growth and differentiation by retinoids. Cancer Res. 1994 Apr 1;54(7 Suppl):1987s–1990s. [PubMed] [Google Scholar]
  23. Monks A., Scudiero D., Skehan P., Shoemaker R., Paull K., Vistica D., Hose C., Langley J., Cronise P., Vaigro-Wolff A. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst. 1991 Jun 5;83(11):757–766. doi: 10.1093/jnci/83.11.757. [DOI] [PubMed] [Google Scholar]
  24. Nagy L., Thomázy V. A., Chandraratna R. A., Heyman R. A., Davies P. J. Retinoid-regulated expression of BCL-2 and tissue transglutaminase during the differentiation and apoptosis of human myeloid leukemia (HL-60) cells. Leuk Res. 1996 Jun;20(6):499–505. doi: 10.1016/0145-2126(95)00118-2. [DOI] [PubMed] [Google Scholar]
  25. Nicholson D. W., Ali A., Thornberry N. A., Vaillancourt J. P., Ding C. K., Gallant M., Gareau Y., Griffin P. R., Labelle M., Lazebnik Y. A. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37–43. doi: 10.1038/376037a0. [DOI] [PubMed] [Google Scholar]
  26. Picus J., Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol. 1999 Oct;26(5 Suppl 17):14–18. [PubMed] [Google Scholar]
  27. Pisani F., Del Poeta G., Aronica G., Venditti A., Caravita T., Amadori S. In vitro down-regulation of bcl-2 expression by all-trans retinoic acid in AML blasts. Ann Hematol. 1997 Oct;75(4):145–147. doi: 10.1007/s002770050332. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Savarese D., Taplin M. E., Halabi S., Hars V., Kreis W., Vogelzang N. A phase II study of docetaxel (Taxotere), estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: preliminary results of cancer and leukemia group B Trial 9780. Semin Oncol. 1999 Oct;26(5 Suppl 17):39–44. [PubMed] [Google Scholar]
  30. Seiter K., Feldman E. J., Dorota Halicka H., Deptala A., Traganos F., Burke H. B., Hoang A., Goff H., Pozzuoli M., Kancherla R. Clinical and laboratory evaluation of all-trans retinoic acid modulation of chemotherapy in patients with acute myelogenous leukaemia. Br J Haematol. 2000 Jan;108(1):40–47. doi: 10.1046/j.1365-2141.2000.01804.x. [DOI] [PubMed] [Google Scholar]
  31. Shapiro G. I., Harper J. W. Anticancer drug targets: cell cycle and checkpoint control. J Clin Invest. 1999 Dec;104(12):1645–1653. doi: 10.1172/JCI9054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shtil A. A., Mandlekar S., Yu R., Walter R. J., Hagen K., Tan T. H., Roninson I. B., Kong A. N. Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells. Oncogene. 1999 Jan 14;18(2):377–384. doi: 10.1038/sj.onc.1202305. [DOI] [PubMed] [Google Scholar]
  33. Sinha A. A., Blackard C. E., Seal U. S. A critical analysis of tumor morphology and hormone treatments in the untreated and estrogen-treated responsive and refractory human prostatic carcinoma. Cancer. 1977 Dec;40(6):2836–2850. doi: 10.1002/1097-0142(197712)40:6<2836::aid-cncr2820400614>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  34. Skehan P., Storeng R., Scudiero D., Monks A., McMahon J., Vistica D., Warren J. T., Bokesch H., Kenney S., Boyd M. R. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990 Jul 4;82(13):1107–1112. doi: 10.1093/jnci/82.13.1107. [DOI] [PubMed] [Google Scholar]
  35. Wang T. H., Wang H. S., Ichijo H., Giannakakou P., Foster J. S., Fojo T., Wimalasena J. Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways. J Biol Chem. 1998 Feb 27;273(9):4928–4936. doi: 10.1074/jbc.273.9.4928. [DOI] [PubMed] [Google Scholar]

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