Structure-activity relationship of butyrate analogues on apoptosis, proliferation and histone deacetylase activity in HCT-116 human colorectal cancer cells.
1. Butyrate, a bacteria fermentative product in the colonic lumen, has been shown to produce a wide variety of biological effects in human cancer cells in vitro. However, there are pharmacological drawbacks associated with the use of butyrate therapy and there are limited published data on the structure-activity relationship of butyrate analogues in colorectal cancer cells. Previously, we determined structure-activity relationship using HT-29 human colorectal cancer cells. However, it was viewed as important to explore similar relationships in another colorectal cancer cell line. 2. Therefore, in the present study, the in vitro structure-activity relationship of butyrate analogues was examined by investigating their effects on apoptosis, cell proliferation, histone deacetylase (HDAC) activity and lactate dehydrogenase (LDH) leakage as a measure of cell toxicity in HCT-116 human colorectal cancer cells. 3. Of the 32 analogues tested, only 4-benzoylbutyrate, 3-benzo-ylpropionate, 4-(4-nitrophenyl)butyrate and 3-(4-fluorobenzoyl)propionate exhibited comparable biological effects to butyrate. The common structural properties of the compounds of interest were to lack amino or hydroxyl substitutions at the 2-, 3- and/or 4-position of the aliphatic moiety of butyrate. 4. The present study reveals a dissociation between the induction of apoptosis, inhibition of cell proliferation, HDAC activity and LDH leakage. The results indicate differential responses of butyrate analogues in HT-29 and HCT-116 colorectal cancer cells.
Ooi
Cheng Cheng
CC
CSIRO Preventative Health Flagship, Adelaide, South Australia, Australia.
Good
Norm M
NM
Williams
Desmond B
DB
Lewanowitsch
Tanya
T
Cosgrove
Leah J
LJ
Lockett
Trevor J
TJ
Head
Richard J
RJ
D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000503:physiopathology*; D003510:Cyclohexanes; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D013329:Structure-Activity Relationship
D002087:Butyrates; D003510:Cyclohexanes; D056572:Histone Deacetylase Inhibitors; C506365:Cyclohexane; D007770:L-Lactate Dehydrogenase; D006655:Histone Deacetylases