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J. Biol. Chem., Vol. 277, Issue 39, 35869-35879, September 27, 2002
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From the Division of Toxicology, Leiden Amsterdam Center for Drug
Research, Leiden University, Leiden 2300, The Netherlands
Various anticancer drugs cause mitochondrial
perturbations in association with apoptosis. Here we investigated the
involvement of caspase- and Bcl-2-dependent pathways in
doxorubicin-induced mitochondrial perturbations and apoptosis. For this
purpose, we set up a novel three-color flow cytometric assay using
rhodamine 123, annexin V-allophycocyanin, and propidium iodide to
assess the involvement of the mitochondria in apoptosis caused by
doxorubicin in the breast cancer cell line MTLn3. Doxorubicin-induced
apoptosis was preceded by up-regulation of CD95 and CD95L and a
collapse of mitochondrial membrane potential (
Differential Regulation of Doxorubicin-induced
Mitochondrial Dysfunction and Apoptosis by Bcl-2 in Mammary
Adenocarcinoma (MTLn3) Cells*
) occurring prior
to phosphatidylserine externalization. This drop in was
independent of caspase activity, since
benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone
did not inhibit it.
Benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone also
blocked activation of caspase-8, thus excluding an involvement of the
death receptor pathway in dissipation. Furthermore, although
overexpression of Bcl-2 in MTLn3 cells inhibited apoptosis, dissipation
of was still observed. No decrease in was observed in
cells undergoing etoposide-induced apoptosis. Immunofluorescent analysis of and cytochrome c localization on a
cell-to-cell basis indicates that the collapse of and cytochrome
c release are mutually independent in both normal and
Bcl-2-overexpressing cells. Together, these data indicate that
doxorubicin-induced dissipation of the mitochondrial membrane potential
precedes phosphatidylserine externalization and is independent of a
caspase- or Bcl-2-controlled checkpoint.
*
This work was supported by a fellowship from the Royal
Netherlands Academy for Arts and Sciences (to B. v. d. W.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Toxicology, LACDR, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands. Tel.: 31-71-5276223; Fax:
31-71-5276292; E-mail: b.water@LACDR.LeidenUniv.nl.
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