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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4096-4108
RAPID COMMUNICATION
Purified Photoproducts of Merocyanine 540 Trigger Cytochrome C Release
and Caspase 8-Dependent Apoptosis in Human Leukemia and Melanoma Cells
Shazib Pervaiz,
Mohamed A. Seyed,
Jayshreekumari L. Hirpara,
Marie-Véronique Clément, and
Kok W. Loh
From the Department of Physiology, National University of Singapore,
Singapore; and the Oncology Research Institute, NUMI, Singapore.
If the interplay between caspase proteases and mitochondria decide
the fate of the cell during apoptosis, they may constitute useful
molecular targets for novel drug design. We have shown that
photoactivated merocyanine 540 (pMC540) triggers caspase-mediated apoptosis in HL60 leukemia and M14 melanoma cells. Because pMC540 is a
mixture of photoproducts, we set out to purify the biologically active
component(s) from this mixture and to investigate their ability to
directly activate intracellular caspases and/or trigger mitochondrial
events associated with apoptosis. Two photoproducts, namely C1 and C2,
purified and characterized by mass spectroscopy and nuclear magnetic
resonance (NMR) analysis, effectively induced apoptosis in
HL60 and M14 cells. Interestingly, both C1 and C2 induced
non-receptor-dependent activation of caspase 8, which was responsible
for the downstream activation of caspase 3 and cell death. Both
compounds induced the release of cytochrome C from mitochondria of
tumor cells and from purified rat liver mitochondria; however,
different mechanisms were operative in cytochrome C translocation in
response to C1 or C2. C1-induced cytochrome C release was mediated by
the mitochondrial permeability transition (MPT) pore and accompanied by
a decrease in mitochondrial transmembrane potential
(  m), whereas cytochrome C release in response to C2
was independent of MPT pore opening. These findings do not exclude the
possibility that changes in mitochondrial m are
critical for apoptosis in some instances, but support the notion that
this may not be a universal step in the apoptotic process. Thus,
identification of two novel anticancer agents that directly activate
effector components of the apoptotic pathway could have potential
implications for the development of newer chemotherapeutic drugs.
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