Abstract
4-Sodium phenylbutyrate (4-PBA) has been used for many years in the treatment of urea cycle defects and has recently been studied as a chemotherapeutic agent for certain malignancies. 4-PBA has been shown to cause growth arrest, cellular differentiation, and apoptosis in certain malignant cells. Recently, it was shown that IB3-1 cells (a cystic fibrosis cell line, Δ508/W128X) treated with 4-PBA demonstrated a partial correction of the cystic fibrosis chloride channel defect. We were interested in evaluating the effect of 4-PBA on cell growth and cell cycle regulation in IB3-1 cells treated with 2 to 10 mM concentrations. We found that cells treated with 2 mM concentrations of 4-PBA for 96 h underwent a significant decrease in cell growth (P < .007). Using flow cytometry, we were able to demonstrate that growth arrest occurred at the G1 phase of the cell cycle. This was detected as early as 24 h in IB3-1 cells treated with 5 mM 4-PBA (P< .03). Furthermore, the percentage of IB3-1 cells with less than a 2N DNA content increased with higher concentrations of 4-PBA, although this was not associated with an increase in apoptosis. Finally, p21Waf1/Cip1/Sdi1 protein levels were induced in IB3-1 cells receiving 2 and 5 mM concentrations of 4-PBA as early as 24 h of exposure, suggesting that G1 phase growth arrest in IB3-1 cells treated with 4-PBA is regulated through the p21Waf1/Cip1/Sdi1 pathway.
Footnotes
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Send reprint requests to: S. A. McGrath-Morrow, M.D., Department of Pediatric Pulmonary, Johns Hopkins Hospital, Park 316/600 N. Wolfe St., Baltimore, MD 21287-2533. E-mail: smorrow{at}jhmi.edu
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↵1 S.A.M. was supported by National Institutes of Health-KO8 Award HL03624 and an American Lung Association Research grant.
- Abbreviations:
- 4-PBA
- 4-sodium phenylbutyrate
- CF
- cystic fibrosis
- CFTR
- cystic fibrosis transmembrane conductance regulator
- ER
- endoplasmic reticulum
- FITC
- fluorescein isothiocyanate
- 2N
- normal diploid
- Received March 7, 2000.
- Accepted May 3, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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