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Vol. 302, Issue 1, 8-17, July 2002
Department of Pharmaceutical Sciences, Medical University of South
Carolina, Charleston, South Carolina
The chemotherapeutic cisplatin causes renal dysfunction and renal
proximal tubular cell (RPTC) apoptosis. The goal of these studies was
to examine the role of p53, caspase 3, 8, and 9, and mitochondria in
the signaling of cisplatin-induced apoptosis. Cisplatin (50 µM)
produced time-dependent apoptosis in RPTCs, causing cell shrinkage, a
50-fold increase in caspase 3 activity, a 4-fold increase in
phosphatidylserine externalization, and 5- and 15-fold increases in
chromatin condensation and DNA hypoploidy, respectively. Mitochondrial
membrane potential and ATP levels did not change at any time during
cisplatin exposure. Caspase 8 and 9 activities also did not increase
during treatment. Cisplatin increased nuclear p53 expression 4 h
after treatment, preceding both caspase 3 activation and chromatin
condensation. Treatment with the p53 inhibitor
-2-(2-imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-1-p-tolylethanone (PFT) before cisplatin exposure inhibited p53 nuclear expression at 4, 8, and 12 h and inhibited phosphatidylserine externalization and
caspase 3 activation at 12 h. Neither DEVD-fmk nor ZVAD-fmk inhibited cisplatin-induced p53 nuclear expression. Both DEVD-fmk and
ZVAD-fmk completely inhibited caspase 3 activity but, like PFT,
partially inhibited cisplatin-induced chromatin condensation, annexin V
labeling, and DNA hypoploidy after 24 h. These data demonstrate
that at least 50% of cisplatin-induced apoptosis in RPTC is mediated
by p53 and that p53 activates caspase 3 independently of either caspase
9 or 8 or mitochondrial dysfunction. Furthermore, 50% of
cisplatin-induced RPTC apoptosis is independent of p53 and caspases 3, 8, and 9.
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