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

In English

Författare

  • A R Olsson
  • Hanna Lindgren
  • Ronald Pero
  • Tomas Leanderson

Summary, in English

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.

Avdelning/ar

  • Immunology

Publiceringsår

2002

Språk

Engelska

Sidor

971-978

Publikation/Tidskrift/Serie

British Journal of Cancer

Volym

86

Issue

6

Dokumenttyp

Artikel i tidskrift

Förlag

Nature Publishing Group

Ämne

  • Cancer and Oncology

Nyckelord

  • 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

Status

Published

Forskningsgrupp

  • Immunology

ISBN/ISSN/Övrigt

  • ISSN: 1532-1827