In recent years, several
antioxidant substances have been found to have an antiproliferative effect on various types of
carcinomas. α-
lipoic acid (ALA) induces apoptosis in several types of
cancer cell lines, but it is difficult to apply α-
lipoic acid in clinical use as it is easily oxidized and unstable. Recently, we succeeded in synthesizing the α-
lipoic acid derivative
sodium N-[6,8-dimercaptooctanoyl]-2-aminoethanesulfonate
zinc complex (
DHL-TauZnNa), which has highly stable
antioxidant effects. We investigated whether
DHL-TauZnNa elicits its antiproliferative effects in vivo and in vitro by inducing apoptosis, autophagy or cell cycle arrest, and we analyzed the expression of
proteins related to these phenomena and their phosphorylation in HT-29 human
colon cancer cells. Subcutaneously administered
DHL-TauZnNa treatment applied daily for 41 days significantly inhibited
tumor growth by 43% in a xenograft mouse model (P=0.0271).
DHL-TauZnNa significantly reduced cell viability over that of controls in the
trypan-blue exclusion test in a time- and dose-dependent manner (P<0.05).
DHL-TauZnNa increased the proportion of cells in S phase and decreased that of cells in G0/G1 phase in the cell cycle analysis of HT-29 cells. Although
DHL-TauZnNa did not increase
caspase-3/7 activity and DNA fragmentation in flow cytometry analysis, it increased the expression of
microtubule-associated protein light chain 3-II. Autophagosomes and autolysosomes were observed by electron microscopy in the cytoplasm of HT-29 cells treated with
DHL-TauZnNa. These results suggest that
DHL-TauZnNa inhibited the proliferation of HT-29 cells through the mechanisms of G2/M cell cycle arrest and autophagy but not that of apoptosis. The newly synthesized ALA derivative
DHL-TauZnNa may be expected to become a novel
cancer therapeutic strategy through its induction of autophagy.