Exposure to a deuterated analogue of phenylbutyrate retards S-phase progression in HT-29 colon cancer cells

Kevin O. Clarke, Susan M. Ludeman, James B. Springer, O. Michael Colvin, Michael Lea, Lawrence E. Harrison

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Differentiation agents that induce neoplastic cells to regain a normal phenotype and/or cause growth arrest without significantly affecting normal cells represent an attractive option for cancer treatment. Analogues of short chain fatty acids, such as phenylbutyrate (PB), have been studied as clinically relevant agents. In an attempt to improve its pharmacokinetic profile, structural modifications of PB and other fatty acids have been studied. We hypothesize that strategic isotopic modification of PB would result in a longer half-life and thus translate into a more potent differentiation agent for clinical use. Using a colon cancer model, we demonstrated that 2,2,3,3-tetradeuterated PB (D4PB) significantly increased induction of apoptosis and inhibition of cell proliferation as compared with PB and butyrate. Difference in potency could not be explained by the effect of D4PB on the expression of specific regulatory proteins of the apoptotic cascade or from the inhibitory effect of D4PB on histone deacetylase activity. Interestingly, exposure of HT-29 colon cancer cells to D4PB resulted in a slowing of S transit, in contrast to butyrate and PB, which induced a G2/M cell cycle block. This difference in cell cycle effect may explain the differences seen in the potency of the phenotypic changes seen with treatment with D4PB. Further studies are needed to elucidate the mechanisms underlying effects of D4PB on the cell cycle.

Original languageEnglish (US)
Pages (from-to)1054-1064
Number of pages11
JournalJournal of Pharmaceutical Sciences
Volume91
Issue number4
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

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Phenylbutyrates
S Phase
Colonic Neoplasms
Cell Cycle
Butyrates
Histone Deacetylases
Volatile Fatty Acids
Half-Life
Fatty Acids
Pharmacokinetics
Cell Proliferation
Apoptosis
Phenotype
Growth
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Clarke, Kevin O. ; Ludeman, Susan M. ; Springer, James B. ; Michael Colvin, O. ; Lea, Michael ; Harrison, Lawrence E. / Exposure to a deuterated analogue of phenylbutyrate retards S-phase progression in HT-29 colon cancer cells. In: Journal of Pharmaceutical Sciences. 2002 ; Vol. 91, No. 4. pp. 1054-1064.
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Exposure to a deuterated analogue of phenylbutyrate retards S-phase progression in HT-29 colon cancer cells. / Clarke, Kevin O.; Ludeman, Susan M.; Springer, James B.; Michael Colvin, O.; Lea, Michael; Harrison, Lawrence E.

In: Journal of Pharmaceutical Sciences, Vol. 91, No. 4, 01.01.2002, p. 1054-1064.

Research output: Contribution to journalArticle

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