1. ¹Institute of Carcinogenesis, Blokhin Cancer Research Center, Kashirskoye shosse 24, Moscow 115478, Russia
2. ²Engelhardt Institute of Molecular Biology, Moscow, Russia
3. ³Moscow Center of Medical Studies, University of Oslo, Moscow, Russia

Correspondence: BP Kopnin, E-mail: bkopnin@yahoo.com

Received 16 June 2004; Revised 4 August 2004; Accepted 4 August 2004; Published online 11 October 2004.

Abstract

Exposure to asbestos fibers increases the risk of development of mesotheliomas and lung carcinomas, but not fibrosarcomas. We present data suggesting that resistance of fibroblasts to asbestos-induced carcinogenesis is likely to be connected with their lower ability to generate reactive oxygen species (ROS) in response to asbestos exposure and stricter control of proliferation of cells bearing asbestos/ROS-induced injuries. In fact, chrysotile (Mg₆Si₄O₁₀(OH)₈) asbestos exposure (5–10 g/cm²) increased intracellular ROS and 8-oxo-guanine contents in rat pleural mesothelial cells, but not in lung fibroblasts. Simultaneously, moderate dosages of chrysotile and other agents increasing ROS levels (hydrogen peroxide, H₂O₂ and ethyl-methanesulfonate, EMS) inhibited cell cycle progression, in particular G1-to-S transition, in fibroblasts, but not in mesothelial cells. The arrested fibroblasts underwent cell death, while the majority of chrysotile-treated mesothelial cells survived. The differences in cell cycle response to asbestos/ROS-induced injuries correlated with distinct activity of p53-p21^Cip1/Waf1 pathway in the two cell types. Chrysotile, H₂O₂ and EMS caused p53 upregulation in both cell types, but mesothelial cells, unlike fibroblasts, showed no accumulation of p21^Cip1/Waf1. Of note, treatment with doxorubicin caused similar p53-dependent p21^Cip1/Waf1 upregulation and cell cycle arrest in both cell types. This suggests differential response of fibroblasts and mesothelial cells specifically to asbestos/ROS exposure rather than to all DNA-damaging insults.