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- Title
Etoposide (VP-16) sensitizes p53-deficient human non-small cell lung cancer cells to caspase-7-mediated apoptosis.
- Authors
Chiu, C.-C.; Lin, C.-H. M. Y.; Fang, K.
- Abstract
Human non-small-cell-lung-cancer (NSCLC) cells of p53-null genotype were exposed to low-dosage topoisomearse II inhibitor etoposide (VP-16). The cellular proliferation rate could be effectively inhibited by VP-16 in dose-dependent manner. The effective drug concentration for growth inhibition could be as low as 0.5 µ M and the apoptotic phenotype became evident 48 h later. In H1299 cells, VP-16-induced cytotoxic effect was demonstrated associated with apoptosis that disappeared when restored with wild-type p53. Cell cycle analysis revealed that, upon VP-16 induction, cell death began with growth arrest by accumulating cells at the G2-M phase. The cells at sub-G1 phase increased at the expense of those at G2-M transition state. To assess the regulation of cell cycle modulators, western blot analysis of H1299 cell lysates showed the release of apoptosis initiator, cytochromecand apaf-1 hours following drug induction. The cleavage of downstream effectors, procaspase-9 and procaspase-7, but not procaspase-3, was accompanied with proteolysis of poly-(ADP-ribose) polymerase (PARP). VP-16-activated procaspase-7 cleavage was abrogated in cells with ectopically expressed p53.On the other hand, the inhibited procaspase-7 fragmentation by caspase-specific inhibitor reversed apoptotic phenotype caused by drug induction. Thus, VP-16-induced apoptotic cell death was contributed by caspase-7 activation in p53-deficient human NSCLC cells.
- Subjects
LUNG cancer; CANCER cells; PHENOTYPES; CELL cycle; GENETIC research; APOPTOSIS
- Publication
Apoptosis, 2005, Vol 10, Issue 3, p643
- ISSN
1360-8185
- Publication type
Article
- DOI
10.1007/s10495-005-1898-8