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ToxSci Advance Access published online on March 1, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj146
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received November 17, 2005
Accepted February 2, 2006

In Vitro Toxicology

Mechanisms of Induction of Cell Cycle Arrest and Cell Death by Cryptolepine in Human Lung Adenocarcinoma A549 Cells

Huijun Zhu 1 * and Nigel J Gooderham 1

1 Biological Chemistry (Molecular Toxicology), Faculty of Natural Sciences, Imperial College London, SW7 2AZ, UK

* To whom correspondence should be addressed.
Huijun Zhu, E-mail: h.zhu{at}cranfield.ac.uk


  Abstract

We investigated p53-dependent and independent molecular events associated with cell cycle alteration and cell death in human lung adenocarcinoma A549 cells using cryptolepine, a DNA damaging agent. After 24-h treatment, cryptolepine caused an accumulation of p53 at concentrations 1.25 -10 µM and induction of p21Cip1/WAF1 but only at concentrations up to 5 µM. P21Cip1/WAF1 was also strongly induced by cryptolepine (2.5-5 µM) in cells with p53 largely ablated via siRNA-mediated gene silencing. Cryptolepine induced G1 phase block at 1.25-2.5 µM, S phase and G2/M phase block at 2.5-5 µM, and cell death at 10 µM. The dead cells displayed condensed and fragmented nuclei, features of apoptosis. Wortmannin, an inhibitor of ataxia telangiectasia-mutated (ATM) and DNA-dependent protein kinase (DNA-PK), caused cell cycle arrest at G1 phase without inducing p53 and P21Cip1/WAF1 expression and cell death. The addition of wortmannin partially prevented cryptolepine-induced expression of p53 and P21Cip1/WAF1 together with the S-phase block, and sensitised cells to induction of cell death. NU7026, a DNA-PK specific inhibitor, showed no induction of cell cycle arrest and apoptosis, nor the expression of p53 and P21Cip1/WAF1. The presence of NU7026 caused further reduction of cells in G1 phase induced by cryptolepine at 5 µM without affecting the induction of p53 and P21Cip1/WAF1 and cell death.

This study using A549 cell as a model demonstrated that cryptolepine selects different molecular pathways to cell cycle checkpoint activation in a dose specific manner and evokes a wortmannin sensitive anti-apoptosis response.

Keywords: ATM; DNA-PK; A549 cells; p21Cip1/WAF1; p53; cryptolepine.
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