Altered maturation of dendritic cells by taxol, an anticancer drug

Joo, Hong-Gu

  • Published : 20030000

Abstract

Taxol is a clinically useful anticancer drug against a variety of cancers. Although it has been known that taxol induces the apoptosis of cancer cells through cytochrome C release and the activation of caspases, the effect of taxol on dendritic cells (DCs) has not been studied. In this study, taxol enhanced the expression of MHC class II on DCs, compared to medium-treated immature DCs. Surprisingly, the viability of DCs was not decreased by taxol, whereas that of cancer cells was. It was confirmed that taxol did not induce the apoptosis of DCs based on annexin V-FITC/propidium iodide (PI) staining assay. Since previous study demonstrated that taxol induced the production of nitric oxide (NO) related to the viability of DCs, the level of NO from taxol-treated DCs was determined. Any significant amount of NO was not detected. Although taxol enhanced the expression of a maturation marker, MHC class II molecules, it strikingly inhibited the proliferation of splenic T lymphocytes activated by DCs. Taken together, this study demonstrated that taxol induced an altered maturation of DCs, the increase of MHC class II molecule but the inhibition of proliferation of splenic T lymphocytes. It is suggested that taxol may induce the immunosuppression in patients with cancer by the inhibition of DC-activated T cell proliferation, but not by the direct killing of DCs.

Keywords

References

  1. Almand, B., Resser, J. R., Lindman, B., Nadaf, S., Clark, J. I., Kwon, E. D., Carbone, D. P. and Gabrilovich, D. I. Clinical significance of defective dendritic cell differentiation in cancer. Clin. Cancer Res. 2000, 6, 1755-1766.
  2. Dieckmann, D., Plottner, H., Berchtold, S., Berger, T. and Schuler, G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J. Exp. Med. 2001, 193, 1303-1310.
  3. Ding, A. H., Porteu, F., Sanchez, E. and Nathan, C. F. Shared actions of endotoxin and taxol on TNF receptors and TNF release. Science 1990, 248, 370-372.
  4. Eisenhauer, E. A. and Vermorken, J. B. The taxoids. Comparative clinical pharmacology and therapeutic potential. Drugs 1998, 55, 5-30.
  5. Ettinger, D. S. Taxol in the treatment of lung cancer. J. Natl. Cancer Inst. Monogr 1993, 15, 177-179.
  6. Inaba, K., Inaba, M., Romani, N., Aya, H., Deguchi, M., Ikehara, S., Muramatsu, S. and Steinman, R. M. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 1992, 176, 1693-1702.
  7. Joo, H. -G., Goedegebuure, P. S., Sadanaga, N., Nagoshi, M., Bernstorff, W. and Eberlein, T. J. Expression and function of galectin-3, a beta-galactoside-binding protein in activated T lymphocytes. J. Leukocyte Biol. 2001, 69, 555-564.
  8. Lu, L., Bonham, C. A., Chambers, F. G., Watkins, S. C., Hoffman, R. A., Simmons, R. L. and Thomson, A. W. Induction of nitric oxide synthase in mouse dendritic cells by IFN-gamma, endotoxin, and interaction with allogeneic T cells: nitric oxide production is associated with dendritic cell apoptosis. J. Immunol. 1996, 157, 3577-3586.
  9. MacKeigan, J. P., Collins, T. S. and Ting, J. P. MEK inhibition enhances paclitaxel-induced tumor apoptosis. J. Biol. Chem. 2000, 275, 38953-38956.
  10. Martin, S. J., Reutelingsperger, C. P., McGahon, A. J., Rader, J. A., van Schie, R. C., LaFace, D. M. and Green, D. R. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J. Exp. Med. 1995, 182, 1545-1556.
  11. Morstyn, G. and Burgess, A. W. Hematopoietic growth factors: a review. Cancer Res. 1988, 48, 5624-5637.
  12. Mullins, D. W., Burger, C. J. and Elgert, K. D. Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through nitric oxide. J. Immunol. 1999, 162, 6811-6818.
  13. Munn, D. H., Sharma, M. D., Lee, J. R., Jhaver, K. G., Johnson, T. S., Keskin, D. B., Marshall, B., Chandler, P., Antonia, S. J., Burgess, R., Slingluff, C. L Jr. and Mellor, A. L. Potential regulatory function of human dendritic cells expressing indoleamine 2, 3-dioxygenase. Science 2002, 297, 1867-1870.
  14. Perera, P. Y., Mayadas, T. N., Takeuchi, O., Akira, S., Zaks-Zilberman, M., Goyert, S. M. and Vogel, S. N. CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxolinducible gene expression. J. Immunol. 2001, 166, 574-581.
  15. Schiff, P. B., Fant, J. and Horwitz S. B. Promotion of microtubule assembly in vitro by taxol. Nature 1979, 277, 665-667.
  16. Steinman, R. M. and Nussenzweig, M. C. Avoiding horror autotoxicus : the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl. Acad. Sci. USA. 2002, 99, 351-358.