title: DHL‑TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells.
abstract: 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.
authors.affiliation: Department of Gastroenterological Surgery, Oita University Faculty of Medicine, Hasama-machi, Yufu, Oita 879-5593, Japan. htakahiru@oita-u.ac.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hiratsuka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Inomata
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kono
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Norio
authors.initials: N
authors.lastname: Shiraishi
authors.forename: Seigo
authors.initials: S
authors.lastname: Kitano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056831:Coordination Complexes / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C583996:N-(6,8-dimercaptooctanoyl)-2-aminoethanesulfonic zinc complex; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008063:Thioctic Acid