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Volume 272, Number 7, Issue of February 14, 1997 pp. 4252-4260
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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1-(5-Isoquinolinesulfonyl)-2-methylpiperazine Induces Apoptosis in Human Neuroblastoma Cells, SH-SY5Y, through a p53-dependent Pathway

(Received for publication, June 27, 1996, and in revised form, November 15, 1996)

From the Institute of Molecular and Cell Biology, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Republic of Singapore

We have studied the effect of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a protein kinase inhibitor, on the regulation of apoptosis in the human neuroblastoma cell line, SH-SY5Y. H-7 (20-100 µM) induced apoptosis in these cells characterized by DNA fragmentation and chromatin condensation. Immunoblot analyses were performed with specific antibody against BCL-2, BCL-X_S/L, BAX, JUNB, c-JUN, ICH-1_L, c-FOS, RB, CDK-2, and p53. H-7 treatment did not significantly alter the level of these proteins with the exception of p53. 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 harboring 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 H-7 in mediating apoptosis in the SH-SY5Y line expressing a dominant negative mutant of p53 was significantly diminished. Taken together, these data strongly suggest that a p53-dependent mechanism contributes to the cytotoxicity of H-7 in human neuroblastoma cells.

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