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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1773-1780
Induction of mitochondrial permeability transition and cytochrome
C release in the absence of caspase activation is insufficient for
effective apoptosis in human leukemia cells
Jayshree L. Hirpara,
Mohamed A. Seyed,
Kok W. Loh,
Hui Dong,
R. Manjunatha Kini, and
Shazib Pervaiz
From the Department of Physiology, National University of Singapore,
and The Bioscience Centre, National University of Singapore,
Singapore.
Induction of mitochondrial permeability transition (MPT) and
cytosolic translocation of cytochrome C are considered essential components of the apoptotic pathway. Hence, there is the realization that mitochondrial-specific drugs could have potential for use as
chemotherapeutic agents to trigger apoptosis in tumor cells. Recently,
we showed that photoproducts of merocyanine 540 (pMC540) induced tumor
cell apoptosis. In this study, we focused on identifying mitochondrial-specific compounds from pMC540 and studied their apoptotic potential. One purified fraction, C5, induced a drop in
mitochondrial transmembrane potential and cytosolic
translocation of cytochrome C in HL60 human leukemia cells. Moreover,
the addition of C5 to purified rat liver mitochondria induced MPT as
indicated by mitochondrial matrix swelling, which was completely
inhibited by cyclosporin A, an inhibitor of the inner-membrane
pore. Supernatant of C5-treated mitochondria showed a dose-dependent
increase in cytochrome C, which was also inhibited in the presence of
cyclosporin A, strongly indicating a direct effect on the
inner-membrane pore. Despite the strong mitochondrial reactivity, C5
elicited minimal cytotoxicity (less than 25%) against HL60 leukemia
and M14 melanoma cells because of inefficient caspase activation.
However, prior exposure to C5 significantly enhanced the apoptotic
response to etoposide or the CD95 receptor. Thus, we demonstrate that
MPT induction and cytochrome C release by the novel compound C5, in the
absence of effective caspase activation, is insufficient for triggering
efficient apoptosis in tumor cells. However, when used in combination
with known apoptosis inducers, such compounds could enhance the
sensitivity of tumor cells to apoptosis.
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