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Mechanism of action for N-substituted benzamide-induced apoptosis.

Olsson, A R; Lindgren, Hanna LU ; Pero, Ronald LU and Leanderson, Tomas LU (2002) In British Journal of Cancer 86(6). p.971-978
Abstract
We have analysed the mechanism of action for induction of apoptosis by N-substituted benzamides using declopramide as a lead compound. We show here that declopramide at doses above 250 microM in the mouse 70Z/3 pre-B cell line or in the human promyeolocytic cancer cell line HL60 induced cytochrome c release into the cytosol and caspase-9 activation. The broad spectrum caspase inhibitor zVADfmk and caspase-9 inhibitor zLEDHfmk inhibited apoptosis and improved cell viability when administrated to cells 1 h before exposure to declopramide, whereas the caspase-8 inhibitor zIEDHfmk had less effect. Also, the over expression of Bcl-2 by transfection in 70Z/3 cells inhibited declopramide-induced apoptosis. Prior to the induction of apoptosis, a... (More)
We have analysed the mechanism of action for induction of apoptosis by N-substituted benzamides using declopramide as a lead compound. We show here that declopramide at doses above 250 microM in the mouse 70Z/3 pre-B cell line or in the human promyeolocytic cancer cell line HL60 induced cytochrome c release into the cytosol and caspase-9 activation. The broad spectrum caspase inhibitor zVADfmk and caspase-9 inhibitor zLEDHfmk inhibited apoptosis and improved cell viability when administrated to cells 1 h before exposure to declopramide, whereas the caspase-8 inhibitor zIEDHfmk had less effect. Also, the over expression of Bcl-2 by transfection in 70Z/3 cells inhibited declopramide-induced apoptosis. Prior to the induction of apoptosis, a G(2)/M cell cycle block was induced by declopramide. The cell cycle block was also observed in the presence of broad spectrum caspase inhibitor zVADfmk and in a transfectant expressing high levels of Bcl-2. Furthermore, while p53 was induced in 70Z/3 cells by declopramide, neither the apoptotic mechanism nor the G(2)/M cell cycle block were dependent on p53 activation since both effects were also seen in p53 deficient HL60 cells after addition of declopramide. (Less)
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organization
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Contribution to journal
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published
subject
keywords
G2 Phase : drug effects, HL-60 Cells, Metoclopramide : pharmacology, Human, Mitosis : drug effects, Procainamide : analogs & derivatives, Procainamide : pharmacology, Protein p53 : physiology, Benzamides : pharmacology, Proto-Oncogene Proteins c-bcl-2 : physiology, Cytochrome c : secretion, Enzyme Activation, Apoptosis : drug effects, Caspases : metabolism
in
British Journal of Cancer
volume
86
issue
6
pages
971 - 978
publisher
Nature Publishing Group
external identifiers
  • wos:000174932900019
  • scopus:0037128673
ISSN
1532-1827
DOI
10.1038/sj/bjc/6600136
language
English
LU publication?
yes
id
85487805-eb78-455a-a249-141a60681091 (old id 107655)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11953831&dopt=Abstract
date added to LUP
2007-07-18 14:25:55
date last changed
2017-01-01 04:28:37
@article{85487805-eb78-455a-a249-141a60681091,
  abstract     = {We have analysed the mechanism of action for induction of apoptosis by N-substituted benzamides using declopramide as a lead compound. We show here that declopramide at doses above 250 microM in the mouse 70Z/3 pre-B cell line or in the human promyeolocytic cancer cell line HL60 induced cytochrome c release into the cytosol and caspase-9 activation. The broad spectrum caspase inhibitor zVADfmk and caspase-9 inhibitor zLEDHfmk inhibited apoptosis and improved cell viability when administrated to cells 1 h before exposure to declopramide, whereas the caspase-8 inhibitor zIEDHfmk had less effect. Also, the over expression of Bcl-2 by transfection in 70Z/3 cells inhibited declopramide-induced apoptosis. Prior to the induction of apoptosis, a G(2)/M cell cycle block was induced by declopramide. The cell cycle block was also observed in the presence of broad spectrum caspase inhibitor zVADfmk and in a transfectant expressing high levels of Bcl-2. Furthermore, while p53 was induced in 70Z/3 cells by declopramide, neither the apoptotic mechanism nor the G(2)/M cell cycle block were dependent on p53 activation since both effects were also seen in p53 deficient HL60 cells after addition of declopramide.},
  author       = {Olsson, A R and Lindgren, Hanna and Pero, Ronald and Leanderson, Tomas},
  issn         = {1532-1827},
  keyword      = {G2 Phase : drug effects,HL-60 Cells,Metoclopramide : pharmacology,Human,Mitosis : drug effects,Procainamide : analogs & derivatives,Procainamide : pharmacology,Protein p53 : physiology,Benzamides : pharmacology,Proto-Oncogene Proteins c-bcl-2 : physiology,Cytochrome c : secretion,Enzyme Activation,Apoptosis : drug effects,Caspases : metabolism},
  language     = {eng},
  number       = {6},
  pages        = {971--978},
  publisher    = {Nature Publishing Group},
  series       = {British Journal of Cancer},
  title        = {Mechanism of action for N-substituted benzamide-induced apoptosis.},
  url          = {http://dx.doi.org/10.1038/sj/bjc/6600136},
  volume       = {86},
  year         = {2002},
}