Exposure to a deuterated analogue of phenylbutyrate retards S-phase progression in HT-29 colon cancer cells.
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.
Clarke
Kevin O
KO
Department of Surgery, Division of Surgical Oncology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, MSB G588, Newark, New Jersey 07103, USA.
Ludeman
Susan M
SM
Springer
James B
JB
Colvin
O Michael
OM
Lea
Michael A
MA
Harrison
Lawrence E
LE
D017209:Apoptosis / Q000187:drug effects; D003903:Deuterium / Q000737:chemistry; D006131:Growth Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019073:HT29 Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D010654:Phenylbutyrates / Q000737:chemistry* / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects*
D006131:Growth Inhibitors; D010654:Phenylbutyrates; D003903:Deuterium