acetogenins and thiazolyl-blue

In the present study we extracted three isomeric acetogenins (Ace) from the seeds of Annona cherimolia Mill. (Annonaceae) and determined their genotoxic and cytotoxic potential in mice. Our results showed a significant increase in the rate of micronucleated polychromatic erythrocytes induced by Ace with respect to the value for the control group; the effect was less pronounced than that observed with daunorubicin (Dau). To evaluate cytotoxicity, we determined the proportion of polychromatic erythrocytes with respect to the number of normochromatic erythrocytes, and we found an inhibitory effect induced by Ace that was quite similar to that observed with Dau. Besides, by means of the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide test, we also determined the cytotoxicity of Ace in both a normal fibroblast mouse cell line and in a line derived from human colon cancer. In this assay, the strongest decrease in viability corresponded to the malignant cell line. Our results established for the first time the genotoxic capacity of these compounds in vivo, and confirmed their cytotoxic potential in cultured cells.

Topics: Acetogenins; Animals; Annona; Antineoplastic Agents, Phytogenic; Bone Marrow Cells; Cell Survival; Drug Screening Assays, Antitumor; Erythrocytes; Humans; In Vitro Techniques; Isomerism; Lethal Dose 50; Mice; Micronucleus Tests; Mutagens; Seeds; Tetrazolium Salts; Thiazoles

In this study we evaluated a mono-tetrahydrofuranic subgroup of natural acetogenins that had shown in previous enzyme inhibition studies different potency trends compared with the bis-tetrahydrofuranic acetogenin subgroup. The compounds were tested against colon, breast, lung, liver, and ovarian tumor cell lines. A drug-resistant ovarian cell line was also included in the panel. In general the compounds were more potent than doxorubicin. The goal was to determine how well the mitochondrial complex I inhibition correlates with the in vitro antitumor potency of these natural mono-tetrahydrofuranic acetogenins and of some derivatives. The results indicate that both the reduction of the terminal gamma-lactone after its translactonization and the introduction of an hydroxylimine group in the alkyl chain, near the mono-tetrahydrofuranic moiety, increased the antitumor activity, even against the doxorubicin-resistant cell line.

Topics: Acetogenins; Antineoplastic Agents; Cell Line, Tumor; Electron Transport Complex I; Fatty Alcohols; Furans; Humans; Inhibitory Concentration 50; Lactones; Molecular Structure; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Structure-Activity Relationship; Tetrazolium Salts; Thiazoles