title: Cytotoxic effect of thiacarbocyanine dyes on human colon carcinoma cells and inhibition of bovine heart mitochondrial NADH-ubiquinone reductase activity via a rotenone-type mechanism by two of the dyes.
abstract: Five lipophilic-cationic thiacarbocyanine compounds differing in the side chains (methyl-S13, ethyl-S23, propyl-S33, butyl-S43, and pentyl-S53) and a related thiadicarbocyanine compound with ethyl side chains (S25) exhibited a selective cytotoxic effect on human colon carcinoma cells compared to green monkey kidney epithelial cells. The inhibitory concentration for 50% inhibition of growth (IC50) for the carcinoma cells ranged from 13 nM for S13 and S23 to 160 nM for S25. The carcinoma cells were 4- to 100-fold more sensitive than the normal cells. Two of the five compounds, S13 and S23, selectively inhibited NADH oxidase activity with bovine heart submitochondrial particles (SMP). There was no discernable inhibitory effect by the other three thiacarbocyanine compounds on electron transport chain activity. The primary site of inhibition within the respiratory chain for S13 and S23 appeared to be the NADH to coenzyme Q portion of the mitochondrial electron transport chain. Artificial electron acceptors for this segment of respiratory chain were used to localize the inhibitory site. Using SMP, both S13 and S23 inhibited reduction of menadione, duroquinone, and coenzyme Q. Using purified complex I (NADH-ubiquinone reductase) (EC 1.6.99.3), S13 slightly inhibited reduction of juglone, duroquinone, and coenzyme Q, whereas S23 had no effect on any of the substrates. When rotenone-saturated SMP were used, the inhibitory effects of S13, but not S23, on the reduction of menadione were abolished, as was the inhibitory effect of S13 on coenzyme Q reduction when rotenone-insensitive complex I was used as the source of the enzyme. These results suggest that (1) S13 and S23 inhibition of NADH-ubiquinone reductase activity is enhanced by the membrane environment of the enzyme, and (2) the inhibition appears to be in part akin to the inhibiting mode of rotenone.
authors.affiliation: Indiana University School of Medicine, Northwest Center for Medical Education, Gary 46408.
authors.forename: W M
authors.initials: WM
authors.lastname: Anderson
authors.forename: D L
authors.initials: DL
authors.lastname: Delinck
authors.forename: L
authors.initials: L
authors.lastname: Benninger
authors.forename: J M
authors.initials: JM
authors.lastname: Wood
authors.forename: S T
authors.initials: ST
authors.lastname: Smiley
authors.forename: L B
authors.initials: LB
authors.lastname: Chen
mesh_terms: D000818:Animals; D001665:Binding Sites; D002232:Carbocyanines / Q000633:toxicity*; D002417:Cattle; D002460:Cell Line / Q000187:drug effects; D004396:Coloring Agents / Q000633:toxicity*; D004579:Electron Transport / Q000187:drug effects; D042967:Electron Transport Complex I; D006801:Humans; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D008954:Models, Biological; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D012402:Rotenone / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014812:Vitamin K / Q000378:metabolism
chemical_list: D002232:Carbocyanines; D004396:Coloring Agents; D012402:Rotenone; D014812:Vitamin K; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I