Antiproliferative effects of a new α-lipoic acid derivative, DHL-HisZnNa, in HT29 human colon cancer cells in vitro.
OBJECTIVE
α-Lipoic acid has been reported to induce apoptosis in several cancer cell lines. However, it is prone to oxidation, polymerization and desulfurization, and is insoluble in water. In this study an α-lipoic acid derivative, sodium N-(dihydrolipoyl)-l-histidinate zinc complex (DHL-HisZnNa), was synthesized, which can eliminate active oxygen species. The antiproliferative effects of DHL-HisZnNa, on human colon cancer cell HT29 in vitro, were evaluated.


METHODS
Whether DHL-HisZnNa elicits its antiproliferative effects by inducing apoptosis and cell cycle arrest, was investigated. Expressions of cell-cycle-related proteins and their phosphorylation on HT-29 was also analyzed.


RESULTS
DHL-HisZnNa inhibited cancer cell growth in cultures. Cell cycle analysis by flow cytometry showed time-dependent accumulation of HT-29 cells in G1 phase after exposure to DHL-HisZnNa. Analysis of DNA fragmentation did not reveal evidence of apoptosis after exposure to DHL-HisZnNa. Cells treated with DHL-HisZnNa showed an increase in p53 phosphorylation with the Bio-Plex Phosphoprotein assay. DHL-HisZnNa increased protein levels of the cyclin-dependent kinase inhibitor p21 and decreased that of phosphorylated retinoblastoma protein (Rb) by western blot analysis. Results obtained with DHL-HisZnNa are on a single colon cancer cell line and not comparative experiments with α-lipoic acid.


CONCLUSIONS
This is the first study, to our knowledge, to report the antiproliferative effects of DHL-HisZnNa and the molecular mechanisms by which it inhibits growth of HT29.
Oita University Faculty of Medicine, Department of Gastroenterological Surgery, 1-1 Idaigaoka, Yufu, Oita 879-5593, Japan. k-yohei@oita-u.ac.jp
Yohei
Y
Kono
Masafumi
M
Inomata
Satoshi
S
Hagiwara
Takahiro
T
Hiratsuka
Kosuke
K
Suzuki
Hironori
H
Koga
Norio
N
Shiraishi
Takayuki
T
Noguchi
Seigo
S
Kitano
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D016193:G1 Phase / Q000187:drug effects; D019073:HT29 Cells; D006639:Histidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C572452:zinc histidine dithiooctanamide; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006639:Histidine; D008063:Thioctic Acid