Mechanism of action for N-substituted benzamide-induced apoptosis.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/107655
- author
- Olsson, A R ; Lindgren, Hanna LU ; Pero, Ronald LU and Leanderson, Tomas LU
- organization
- publishing date
- 2002
- 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}},
}