Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells
✍ Scribed by Elisa Barbarotto; Federica Corallini; Erika Rimondi; Roberto Fadda; Carlo Mischiati; Vittorio Grill; Mauro Vaccarezza; Claudio Celeghini
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 252 KB
- Volume
- 104
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
Abstract
We have compared the cytotoxic/cytostatic responses of the SKW6.4 lymphoblastoid B‐cells to the alkylating agent chlorambucil, the purine analog fludarabine, the non‐genotoxic activator of the p53 pathway, Nutlin‐3, used alone or in association with the death‐inducing ligand recombinant TRAIL. Exposure to chlorambucil, fludarabine, and Nutlin‐3 induced p53 accumulation and variably affected cell cycle progression in SKW6.4 lymphoblastoid cells. In particular, chlorambucil induced cell cycle accumulation at the G2/M checkpoint; Nutlin‐3 induced early cell cycle arrest at the G1/S checkpoint, while fludarabine showed an intermediate behavior. On the other hand, recombinant TRAIL alone did not affect cell cycle progression but induced a rapid increase of apoptosis. Analysis of the gene expression profile of the p53‐transcriptional targets showed distinct features between chlorambucil, Nutlin‐3 and fludarabine, which likely account for their differential effect on cell cycle in SKW6.4 cells. In particular, chlorambucil upregulated the steady‐state mRNA expression of SFN/14‐3‐3σ, a gene involved in G2/M cell cycle arrest. Of note, all agonists upregulated TRAIL‐R2 expression in SKW6.4 cells both at the mRNA and protein levels. Consistently, pretreatment with chlorambucil, fludarabine and Nutlin‐3 enhanced SKW6.4 sensitivity to TRAIL‐mediated apoptosis. J. Cell. Biochem. 104: 595–605, 2008. © 2007 Wiley‐Liss, Inc.