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Cell Biology International (2009) 33, 1280–1286 (Printed in Great Britain)

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N-Nitrosopiperidine and N-Nitrosodibutylamine induce apoptosis in HepG2 cells via the caspase dependent pathway

Almudena García^a, Paloma Morales^a, Joseph Rafter^b and Ana I. Haza^a*

^aDepartamento de Nutrición, Bromatología y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain
^bDepartment of Biosciences and Nutrition, Karolinska Institutet, Huddinge University Hospital, NOVUM, S-141 86, Huddinge, Sweden

Abstract

The human hepatoma cell line (HepG2) exhibited a dose and time-dependent apoptotic response following treatment with N-Nitrosopiperidine (NPIP) and N-Nitrosodibutylamine (NDBA), two recognized human carcinogens. Our results showed a significant apoptotic cell death (95%) after 24h treatment with NDBA (3.5mM), whereas it was necessary to use high doses of NPIP (45mM) to obtain a similar percentage of apoptotic cells (86%). In addition, both extrinsic (caspase-8) and intrinsic pathway (caspase-9) could be implicated in the N-Nitrosamines-induced apoptosis. This study also addresses the role of reactive oxygen species (ROS) as intermediates for apoptosis signaling. A significant increase in ROS levels was observed after NPIP treatment, whereas NDBA did not induce ROS. However, N-acetylcysteine (NAC) did not block NPIP-induced apoptosis. All these findings suggest that NPIP and NDBA induce apoptosis in HepG2 cells via a pathway that involves caspases but not ROS.

Key words: Apoptosis, Caspases, HepG2 cells, N-Nitrosamines, Reactive oxygen species.

^*Corresponding author. Tel.: +34 91 394 37 47; fax: +34 91 394 37 43.

Received 19 May 2009/2 July 2009; accepted 27 August 2009