PMID- 10688837
OWN - NLM
STAT- MEDLINE
DCOM- 20000329
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 95
IP  - 5
DP  - 2000 Mar 1
TI  - Induction of mitochondrial permeability transition and cytochrome C release in 
      the absence of caspase activation is insufficient for effective apoptosis in 
      human leukemia cells.
PG  - 1773-80
AB  - 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. (Blood. 
      2000;95:1773-1780)
FAU - Hirpara, J L
AU  - Hirpara JL
AD  - Department of Physiology, National University of Singapore, Singapore.
FAU - Seyed, M A
AU  - Seyed MA
FAU - Loh, K W
AU  - Loh KW
FAU - Dong, H
AU  - Dong H
FAU - Kini, R M
AU  - Kini RM
FAU - Pervaiz, S
AU  - Pervaiz S
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Cytochrome c Group)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Oligopeptides)
RN  - 0 (Pyrimidinones)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (aspartyl-glutamyl-valyl-aspartal)
RN  - 58823-12-4 (merocyanine dye)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - EC 3.4.22.- (Caspases)
RN  - H88EPA0A3N (Staurosporine)
SB  - IM
EIN - Blood. 2014 Jan 9;123(2):300
MH  - Animals
MH  - Antineoplastic Agents/isolation & purification/*pharmacology/radiation effects
MH  - Apoptosis/*drug effects
MH  - Biological Transport/drug effects
MH  - Caspase Inhibitors
MH  - Caspases/*metabolism
MH  - Cyclosporine/pharmacology
MH  - Cytochrome c Group/*metabolism
MH  - Cytosol/enzymology
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - Etoposide/pharmacology
MH  - Fluorescence
MH  - HL-60 Cells/drug effects/metabolism
MH  - Humans
MH  - Intracellular Membranes/*drug effects/metabolism
MH  - Melanoma/*pathology
MH  - Mitochondria/*drug effects/metabolism
MH  - Mitochondria, Liver/drug effects/metabolism/ultrastructure
MH  - Neoplasm Proteins/antagonists & inhibitors/*metabolism
MH  - Oligopeptides/pharmacology
MH  - Permeability/drug effects
MH  - Photochemistry
MH  - Pyrimidinones/chemistry/*pharmacology/radiation effects
MH  - Radiation-Sensitizing Agents/chemistry/*pharmacology/radiation effects
MH  - Rats
MH  - Rats, Wistar
MH  - Signal Transduction/drug effects
MH  - Skin Neoplasms/*pathology
MH  - Staurosporine/pharmacology
MH  - Tumor Cells, Cultured/drug effects/metabolism
EDAT- 2000/02/26 09:00
MHDA- 2000/04/01 09:00
CRDT- 2000/02/26 09:00
PHST- 2000/02/26 09:00 [pubmed]
PHST- 2000/04/01 09:00 [medline]
PHST- 2000/02/26 09:00 [entrez]
AID - S0006-4971(20)67027-6 [pii]
PST - ppublish
SO  - Blood. 2000 Mar 1;95(5):1773-80.