Mutagenesis Advance Access originally published online on October 20, 2008
Mutagenesis 2009 24(2):133-141; doi:10.1093/mutage/gen059
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Published by Oxford University Press on behalf of the UK Environmental Mutagen Society.
Interference of cell cycle progression by zidovudine and lamivudine in NIH 3T3 cells
Division of Biochemical Toxicology 1Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
Zidovudine (3'-azido-3'-deoxythymidine; AZT) and lamivudine [(–)2',3'-dideoxy-3'-thiacytidine; 3TC] are nucleoside reverse transcriptase inhibitors used to treat and prevent human immunodeficiency virus-1 infections. In short-term incubations (<48 h), AZT, but not 3TC, has been shown to interfere with cell cycle progression. In the present study, we examined if these alterations persist during long-term incubations in which cells were exposed to AZT (0–1000 µM) or 3TC (0–500 µM) in continuous culture for up to 5 weeks. In addition, we investigated the reversibility of these effects upon removal of the drugs. Both drugs caused concentration- and time-dependent decreases in the number of viable cells, with the effect being more pronounced with AZT. There was only a slight increase in the number of viable cells treated with AZT for 5 weeks and then allowed a 1-week recovery period; cell viability in cells treated with 3TC returned to control levels during the recovery period. The decrease in viable cells was not due to apoptotic or necrotic cell death, but rather was associated with S and G2/M phase cell cycle arrest. Western blot analysis indicated that AZT treatment caused a decrease in checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2) at all time points. Cyclin-dependent kinase 1 was decreased at later time points, while cyclin A was increased at early times. These data indicate that AZT and, to a lesser extent, 3TC interfere with cell growth by slowing cell cycle progression and that checkpoint proteins Chk1 and Chk2 may play an important role in this delay.
* To whom correspondence should be addressed. Tel: +1 870 543 7612; Fax: +1 870 543 7136; Email: jia-long.fang{at}fda.hhs.gov
Received on July 31, 2008; revised on September 15, 2008; accepted on September 19, 2008.
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  J.-L. Fang and F. A. Beland Long-Term Exposure to Zidovudine Delays Cell Cycle Progression, Induces Apoptosis, and Decreases Telomerase Activity in Human Hepatocytes Toxicol. Sci., September 1, 2009; 111(1): 120 - 130. [Abstract] [Full Text] [PDF]
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