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Mechanism of action for N-substituted benzamide-induced apoptosis.
- Olsson, A R (author)
-
- Lindgren, Hanna (author)
- Lund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups
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- Pero, Ronald (author)
- Lund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups
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- (creator_code:org_t)
- 2002
- 2002
- English.
- In: British Journal of Cancer. - 1532-1827. ; 86:6, s. 971-978
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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
Publication and Content Type
- art (subject category)
- ref (subject category)
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