Investigational New Drugs

, Volume 21, Issue 3, pp 259–268 | Cite as

The mechanism of action of docetaxel (Taxotere®) in xenograft models is not limited to bcl-2 phosphorylation

  • Lisa Ann Kraus
  • Shanti K. Samuel
  • Steven M. Schmid
  • Donald J. Dykes
  • William R. Waud
  • Marie Christine Bissery

Abstract

Docetaxel is a new taxoid compound with a broad spectrum of antitumor activity. Previous studies have shown that in vitro treatment of specific human tumor lines with docetaxel is associated with the phosphorylation and inactivation of the bcl-2 protein and the occurrence of apoptosis. The goal of this study was to examine whether bcl-2 expression is truly required for in vivo responsiveness to docetaxel. The expression and state of phosphorylation of bcl-2 was examined in human MX-1 breast or DU-145 prostate tumors explanted from nu/nu mice treated with docetaxel. The MX-1 cells accumulated in the G2/M phase of the cell cycle and exhibited phosphorylation of bcl-2 after treatment with docetaxel. By Western blot analysis DU-145 prostate tumor cells did not express bcl-2 protein before or following in vivo treatment with docetaxel. However, docetaxel was highly active against the DU-145 tumor xenograft model. Thus, docetaxel induces apoptosis and cell death through a different, bcl-2-independent mechanism in the DU-145 human prostate tumor, indicating that bcl-2 may not have prognostic value for treatment with docetaxel.

bcl-2 docetaxel Taxotere® xenografts 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Denis JN, Greene AE, Guenard D, Gueritte-Voegelein F, Mangatal L, Potier P: A highly efficient, practical approach to natural taxol. J Am Chem Soc 110: 5917–5919, 1988Google Scholar
  2. 2.
    Mangatal L, Adeline MT, Guenard D, Gueritte-Voegelein F, Potier, P: Application of the vicinal oxyamination reaction with asymmetric induction to the hemisynthesis of taxol and analogues. Tetrahedron 45: 4177–4190, 1989Google Scholar
  3. 3.
    Garcia P, Braguer D, Carles G, el Khyari S, Barra Y, de Ines C, Barasoain I, Briand C: Comparative effects of taxol and Taxotere on two different human carcinoma cell lines. Cancer Chemother Pharmacol 34: 335–343, 1994Google Scholar
  4. 4.
    Lavelle F, Bissery MC, Combeau C, Riou JF, Vrignaud P, Andre S: Preclinical evaluation of docetaxel (Taxotere). Semin Oncol 22: 3–16, 1995Google Scholar
  5. 5.
    Stein CA: Mechanisms of action of taxanes in prostate cancer. Semin Oncol 26: 3–7, 1999Google Scholar
  6. 6.
    Pienta KJ: Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin Oncol 28: 3–7, 2001Google Scholar
  7. 7.
    Bissery MC, Guenard D, Gueritte-Voegelein F, Lavelle F: Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res 51: 4845–4852, 1991Google Scholar
  8. 8.
    Bissery MC, Nohynek G, Sanderink GJ, Lavelle F: Docetaxel (Taxotere): a review of preclinical and clinical experience. Part I: Preclinical experience. Anticancer Drugs 6: 339–8, 1995Google Scholar
  9. 9.
    Dykes DJ, Bissery MC, Harrison SD, Waud WR: Response of human tumor xenografts in athymic nude mice to docetaxel (RP 56976, Taxotere). Invest New Drugs 13: 1–11, 1995Google Scholar
  10. 10.
    Friedland D, Cohen J, Miller R, Voloshin M, Gluckman R, Lembersky B, Zidar B, Keating M, Reilly N, Dimitt B: A phase II trial of docetaxel (Taxotere) in hormone-refractory prostate cancer: correlation of antitumor effect to phosphorylation of bcl-2. Semin Oncol 26: 19–23, 1999Google Scholar
  11. 11.
    Picus J, Schultz M: Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 26: 14–18, 1999Google Scholar
  12. 12.
    Kreis W, Budman DR, Fetten J, Gonzales AL, Barile B, Vinciguerra V: Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone refractory prostate carcinoma. Ann Oncol 10: 33–38, 1999Google Scholar
  13. 13.
    Petrylak DP, Macarthur RB, O'Connor J, Shelton G, Judge T, Balog J, Pfaff C, Bagiella E, Heitjan D, Fine R, Zuech N, Sawczuk I, Benson M, Olsson CA: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17: 958–967, 1999Google Scholar
  14. 14.
    Haldar S, Jena N, Croce CM: Inactivation of bcl-2 by phosphorylation. Proc Natl Acad Sci USA 92: 4507–4511, 1995Google Scholar
  15. 15.
    Haldar S, Chintapalli J, Croce CM: Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res 56: 1253–1255, 1996Google Scholar
  16. 16.
    Haldar S, Basu A, Croce CM: bcl2 is the guardian of microtubule integrity. Cancer Res 57: 229–233, 1997Google Scholar
  17. 17.
    Nehme A, Varadarajan P, Sellakumar G, Gerhold M, Niedner H, Zhang Q, Lin X, Christen RD: Modulation of docetaxel-induced apoptosis and cell cycle arrest by all-trans retinoic acid in prostate cancer cells. Br J Cancer 84: 1571–1576, 2001Google Scholar
  18. 18.
    Reed JC: Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol 7: 541–546, 1995Google Scholar
  19. 19.
    Reed JC: bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol 34: 9–19, 1997Google Scholar
  20. 20.
    Schmitt E, Sane AT, Steyaert A, Cimoli G, Bertrand R: The bcl-xL and Bax-alpha control points: modulation of apoptosis induced by cancer chemotherapy and relation to TPCK-sensitive protease and caspase activation. Biochem Cell Biol 75: 301–314, 1997Google Scholar
  21. 21.
    Haldar S, Jena N, DuBois GC, Takayama S, Reed JC, Fu SS, Croce CM: Purification and characterization of the bcl-2 protein. Arch Biochem Biophys 315: 483–488, 1994Google Scholar
  22. 22.
    Yin XM, Oltvai ZN, Korsmeyer SJ: BH1 and BH2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369: 321–323, 1994Google Scholar
  23. 23.
    Miyashita T, Reed JC: bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 52: 5407–5411, 1992Google Scholar
  24. 24.
    Kitada S, Takayama S, De Riel K, Tanaka S, Reed JC: Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of bcl-2 gene expression. Antisense Res Dev 4: 71–79, 1994Google Scholar
  25. 25.
    Pepper C, Bentley P, Hoy T: Regulation of clinical chemoresistance by bcl-2 and bax oncoproteins in B-cell chronic lymphocytic leukaemia. Br J Haematol 95: 513–517, 1996Google Scholar
  26. 26.
    Krajewski S, Blomqvist C, Franssila K, Krajewska M, Wasenius VM, Niskanen E, Nordling S, Reed JC: Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. Cancer Res 55: 4471–4478, 1995Google Scholar
  27. 27.
    Dole MG, Jasty R, Cooper MJ, Thompson CB, Nunez G, Castle VP: bcl-xL is expressed in neuroblastoma cells and modulates chemotherapy-induced apoptosis. Cancer Res 55: 2576–2582, 1995Google Scholar
  28. 28.
    Fang W, Rivard JJ, Ganser JA, LeBien TW, Nath KA, Mueller DL, Behrens TW: bcl-xL rescues WEHI 231 B lymphocytes from oxidant-mediated death following diverse apoptotic stimuli. J Immunol 155: 66–75, 1995Google Scholar
  29. 29.
    Lebedeva I, Rando R, Ojwang J, Cossum P, Stein CA: bcl-xL in prostate cancer cells: effects of overexpression and down-regulation on chemosensitivity. Cancer Res 60: 6052–6060, 2000Google Scholar
  30. 30.
    Costa A, Licitra L, Veneroni S, Daidone MG, Grandi C, Cavina R, Molinari R, Silvestrini R: Biological markers as indicators of pathological response to primary chemotherapy in oral-cavity cancers. Int J Cancer 79: 619–623, 1998Google Scholar
  31. 31.
    Guinan P, Didomenico D, Brown J, Shaw M, Sharifi R, Ray V, Shott S, Rubenstein M: The effect of androgen deprivation on malignant and benign prostate tissue. Med Oncol 14: 145–152, 1997Google Scholar
  32. 32.
    Hermine O, Haioun C, Lepage E, d'Agay MF, Briere J, Lavignac C, Fillet G, Salles G, Marolleau JP, Diebold J, Reyas F, Gaulard P: Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 87: 265–272, 1996Google Scholar
  33. 33.
    Hogarth LA, Hall AG: Increased BAX expression is associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood 93: 2671–2678, 1999Google Scholar
  34. 34.
    Logsdon MD, Meyn RE, Besa PC, Pugh WC, Stephens LC, Peters LJ, Milas L, Cox JD, Cabanillas F, Brisbay S, Andersen M, McDonnell TJ: Apoptosis and the bcl-2 gene family — patterns of expression and prognostic value in stage I and II follicular center lymphoma. Int J Radiat Oncol Biol Phys 44: 19–29, 1999Google Scholar
  35. 35.
    Makris A, Powles TJ, Dowsett M, Osborne CK, Trott PA, Fernando IN, Ashley SE, Ormerod MG, Titley JC, Gregory RK, Allred DC: Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas. Clin Cancer Res 3: 593–600, 1997Google Scholar
  36. 36.
    Sangfelt O, Osterborg A, Grander D, Anderbring E, Ost A, Mellstedt H, Einhorn S: Response to interferon therapy in patients with multiple myeloma correlates with expression of the bcl-2 oncoprotein. Int J Cancer 63: 190–192, 1995Google Scholar
  37. 37.
    De Cesare M, Pratesi G, Giusti A, Polizzi D, Zunino F: Stimulation of the apoptotic response as a basis for the therapeutic synergism of lonidamine and cisplatin in combination in human tumour xenografts. Br J Cancer 77: 434–439, 1998Google Scholar
  38. 38.
    Tang DG, Li L, Chopra DP, Porter AT: Extended survivability of prostate cancer cells in the absence of trophic factors: increased proliferation, evasion of apoptosis, and the role of apoptosis proteins. Cancer Res 58: 3466–3479, 1998Google Scholar
  39. 39.
    Van Brussel JP, van Steenbrugge GJ, Romijn JC, Schroder FH, Mickisch GH: Chemosensitivity of prostate cancer cell lines and expression of multidrug resistance-related proteins. Eur J Cancer 35: 664–671, 1999Google Scholar
  40. 40.
    Griswold DP, Schabel FM, Wilcox WS, Simpson-Herren L, Skipper HE: Success and failure in the treatment of solid tumors. I. Effects of cyclophosphamide (NSC-26271) on primary and metastatic plasmacytoma in the hamster. Cancer Chemother Rep 52: 345–387, 1968Google Scholar
  41. 41.
    Veis DJ, Sentman CL, Bach EA, Korsmeyer SJ: Expression of the bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. J Immunol 151: 2546–2554, 1993Google Scholar
  42. 42.
    Dean PN, Jett JH: Mathematical analysis of DNA distributions derived from flow microfluorometry. J Cell Biol 60: 523–527, 1974Google Scholar
  43. 43.
    Marquardt DW: An algorithm for least-squares estimation of nonlinear parameters. Appl Math 11: 431–441, 1963Google Scholar
  44. 44.
    Pantazis P, Chatterjee D, Wyche J, DeJesus A, Early J, Plaschke S, Giovanella B: Establishment of human prostate tumor xenografts in nude mice and response to 9–nitrocamptothecin in vivo and in vitro does not correlate with the expression of various apoptosis-regulating proteins. J Exp Ther Oncol 1: 322–333, 1996Google Scholar
  45. 45.
    Pratesi G, Polizzi D, Perego P, Dal Bo L, Zunino F: bcl-2 phosphorylation in a human breast carcinoma xenograft: a common event in response to effective DNA-damaging drugs. Biochem Pharmacol 60: 77–82, 2000Google Scholar
  46. 46.
    Schimming R, Mason KA, Hunter N, Weil M, Kishi K, Milas L: Lack of correlation between mitotic arrest or apoptosis and antitumor effect of docetaxel. Cancer Chemother Pharmacol 43: 165–172, 1999Google Scholar
  47. 47.
    Veitia R, Bissery MC, Martinez C, Fellous A: Tau expression in model adenocarcinomas correlates with docetaxel sensitivity in tumour-bearing mice. Br J Cancer 78: 871–877, 1998Google Scholar
  48. 48.
    Van Oosterom AT: Docetaxel (Taxotere): an effective agent in the management of second-line breast cancer. Semin Oncol 22: 22–28, 1995Google Scholar
  49. 49.
    Shirahama T, Sakakura C, Sweeney EA, Ozawa M, Takemoto M, Nishiyama K, Ohi Y, Igarashi Y: Sphingosine induces apoptosis in androgen-independent human prostatic carcinoma DU-145 cells by suppression of bcl-X(L) gene expression. FEBS Lett 407: 97–100, 1997Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Lisa Ann Kraus
    • 1
  • Shanti K. Samuel
    • 1
  • Steven M. Schmid
    • 1
  • Donald J. Dykes
    • 1
  • William R. Waud
    • 1
  • Marie Christine Bissery
    • 2
  1. 1.Southern Research InstituteBirmingham
  2. 2.Aventis OncologyVitry-sur-Seine, CedexFrance

Personalised recommendations