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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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author
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organization
publishing date
type
Contribution to journal
publication status
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
2016-04-01 11:43:15
date last changed
2022-03-12 23:44:50
@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}},
  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}},
  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}},
  doi          = {{10.1038/sj/bjc/6600136}},
  volume       = {{86}},
  year         = {{2002}},
}