Regulation of p53-Dependent Apoptosis in Human Neuroblastoma Cells by Isoquinolines

  • Victor C. Yu
  • Francesca Ronca


We have studied staurosporine and a few other isoquinolines, which are known protein kinases inhibitors, for their ability in regulating the apoptosis in human neuroblastoma cells. Staurosporine and a subset of isoquinolinesulphonamides, including H-7 ([1-(5-Isoquinolinesulfonyl)-2-methylpiperazine]), were found to be able to induce widespread apoptosis, characterized by DNA fragmentation and nuclear condensation, in human neuroblastoma cells, SH-SY5Y, within 24 hours. Surprisingly, exposure of the cells to the H-7, but not staurosporine, caused a dramatic nuclear accumulation of p53. The kinetics of nuclear accumulation of p53 correlates well with the kinetics of induction of apoptosis. The effect of H-7 was further assessed in a group of human cell lines. Only cell lines harbouring the wild-type p53 gene were responsive to the stimulatory effect of H-7 on nuclear accumulation of p53. Furthermore, cell lines carrying a mutated p53 gene were resistant to the cytotoxic effect of H-7. The ability of the compound in mediating the apoptotic response in the SH-SY5Y line expressing a dominant negative mutant of p53 was significantly reduced. These data strongly suggest that a p53-dependent mechanism contributes to the cytoxicity of the H-7 in human neuroblastoma cells. Other PKC inhibitors failed to mediate apoptosis in neuroblastoma cells through the p53 pathway further suggest that a unique H-7 sensitive pathway which is different from the known PKC pathway is responsible for mediating the effect. Thus, the experimental paradigm of apoptosis triggered by H-7 in neuroblastoma cells is likely to be useful for gaining a further understanding of the pathways and mechanisms underlying the apoptotic function of p53.


Nuclear Accumulation Human Neuroblastoma Cell Protein Kinase Inhibitor Human Neuroblastoma Cell Line Vector Control Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bertrand, R., Solary, E., O’Connor, R, Kohn, K.W., and Pommier, Y. (1994) Exp. Cell Res. 211, 314–321.PubMedCrossRefGoogle Scholar
  2. Caelles, C., Helmberg, A., and Karin, M. (1994) Nature 370, 220–223.PubMedCrossRefGoogle Scholar
  3. Davidoff, A.M., Pence, J.C., Shorter, N.A., Iglehart, J.D., and Marks, J.R. (1992) Oncogene 7, 127–133.PubMedGoogle Scholar
  4. Dole, M.G., Jasty, R., Cooper, M.J., Thompson, C.B., Nunez, G., and Castle, V.P. (1995) Cancer Res. 55, 2576–2582.PubMedGoogle Scholar
  5. Donehower, L.A., Harvey, M., Slagle, B.L., McArthur, M.J., Montgomery, C.A., Jr., Butel, J.S., and Bradley, A. (1992) Nature 356, 215–221.PubMedCrossRefGoogle Scholar
  6. El-Deiry, W.S., Tokino, T., Velculescu, V.E., Levy, D.B., Parsons, R., Trent, J.M., Lin, D., Mercer, W.E., Kinzler, K.W., and Vogelstein, B. (1993) Cell 75, 817–825.PubMedCrossRefGoogle Scholar
  7. Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K., and Elledge, S.J. (1993) Cell 75, 805–816.PubMedCrossRefGoogle Scholar
  8. Hidaka, H., Inagaki, M., Kawamoto, S., and Sasaki, Y. (1984) Biochemistry 23, 5036–5041.PubMedCrossRefGoogle Scholar
  9. Hollstein, M., Sidransky, D., Vogelstein, B., and Harris, C.C. (1991) Science 253, 49–53.PubMedCrossRefGoogle Scholar
  10. Hosoi, G., Hara, J., Okamura, T., Osugi, Y, Ishihara, S., Fukuzawa, M., Okada, A., Okada, S., and Tawa, A. (1994) Cancer 73, 3087–3093.PubMedCrossRefGoogle Scholar
  11. Imamura, J., Bartram, C.R., Berthold, F., Harms, D., Nakamura, H., and Koeffler, H.P. (1993) Cancer Res. 53, 4053–4058.PubMedGoogle Scholar
  12. Komuro, H., Hayashi, Y, Kawamura, M., Hayashi, K., Kaneko, Y, Kamoshita, S., Hanada, R., Yamamoto, K., Hongo, T., and Yamada, M. (1993) Cancer Res. 53, 5284–5288.PubMedGoogle Scholar
  13. Miyashita, T. and Reed, J.C. (1995) Cell 80, 293–299.PubMedCrossRefGoogle Scholar
  14. Owen-Schaub, L.B., Zhang, W., Cusack, J.C., Angelo, L.S., Santee, S.M., Fujiwara, T., Roth, J.A., Deisseroth, A.B., Zhang, W.W., and Kruzel, E. (1995) Mol. Cell Biol. 1555, 3032–3040.Google Scholar
  15. Ronca, F., Chan, S.L., and Yu, V.C. (1997) J. Biol. Chem., 272, 4252–4260.PubMedCrossRefGoogle Scholar
  16. Ross, R.A. and Biedler, J.L. (1985) Cancer Res. 45, 1628–1632.PubMedGoogle Scholar
  17. Sádee, W., Yu, V.C., Richards, M.L., Preis, P.N., Schwab, M.R., Brodsky, F.M., and Biedler, J.L. (1987) Cancer Res. 47, 5207–5212.PubMedGoogle Scholar
  18. Seto, M., Sasaki, Y, Sasaki, Y, and Hidaka, H. (1991) Eur. J. Pharmacol. 195, 267–272.PubMedCrossRefGoogle Scholar
  19. Shaulian, E., Zauberman, A., Ginsberg, D., and Oren, M. (1992) Mol Cell Biol. 12, 5581–5592.PubMedGoogle Scholar
  20. Shaulian, E., Haviv, I., Shaul, Y, and Oren, M. (1995) Oncogene 10, 671–680.PubMedGoogle Scholar
  21. Shaw, P., Bovey, R., Tardy, S., Sahli, R., Sordat, B., and Costa, J. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 4495–4499.PubMedCrossRefGoogle Scholar
  22. Vogan, K., Bernstein, M., Leclerc, J.M., Brisson, L., Brossard, J., Brodeur, G.M., Pelletier, J., and Gros, P. (1993) Cancer Res. 53, 5269–5273.PubMedGoogle Scholar
  23. Vogelstein, B. (1990) Nature 348, 681–682.PubMedCrossRefGoogle Scholar
  24. Wyllie, A.H., Kerr, J.F., and Currie, A.R. (1980) Int. Rev. Cytol. 68, 251–306.PubMedCrossRefGoogle Scholar
  25. Xiong, Y, Hannon, G.J., Zhang, H., Casso, D., Kobayashi, R., and Beach, D. (1993) Nature 366, 701–704.PubMedCrossRefGoogle Scholar
  26. Yonish-Rouach, E., Resnitzky, D., Lotem, J., Sachs, L., Kimchi, A., and Oren, M. (1991) Nature 352, 345–347.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Victor C. Yu
    • 1
  • Francesca Ronca
    • 1
  1. 1.Institute of Molecular and Cell BiologyNational University of SingaporeSingaporeRepublic of Singapore

Personalised recommendations