beta-carotene and Leukemia--Promyelocytic--Acute

Three all-trans epoxides of beta-carotene (beta-Car), namely, 5,6-epoxy-beta-carotene (5,6-EC), 5,8-epoxy-beta-carotene (5,8-EC) and 5,6,5',6'-diepoxy-beta-carotene (5,6,5',6'-DEC) were synthesized by treatment of beta-carotene with 3-chloroperoxybenzoic acid, were purified chromatographically, and were characterized. The relative potencies (mean +/- S.D.) of 1 microM compounds in inducing the differentiation of NB4 cells, a cell line that contains the chromosomal transposition t(15;17) characteristic of acute promyelocytic leukemia, after 4 days of incubation were: RA: 1.35 +/- 0.16, 5,6-EC: 0.29 +/- 0.01, 5,8-EC: 0.22 +/- 0.05, 5,6,5',6'-DEC: 0.11 +/- 0.02, beta C: 0.09 +/- 0.01, and the control: 0.06 +/- 0.01. The same order of potencies existed at other concentrations tested and at other incubation times. P values for the differences between the inducing activities of successive pairs of compounds at 1 microM were: RA vs. 5,6-EC, < 0.001; 5,6-EC vs. 5,8-EC, < 0.01; 5,8-EC vs. 5,6,5',6'-DEC, < 0.01; 5,6,5',6'-DEC vs. beta-Car, < 0.10; beta-Car vs. control, < 0.005. Similar P values were also obtained for studies at other concentrations and at other incubation times. The viable cell mass at 4 days was inversely proportional to the extent of differentiation (rs = -1.0). The inducing activities of all compounds were dose-dependent. Thus, the 5,6-monoepoxide of beta-carotene, which has not previously been studied as an inducer, showed higher activity in NB4 cell differentiation than the 5,8-monoepoxide, the 5,6,5',6'-diepoxide, or beta-carotene. Possible explanations of these observations are discussed.

Topics: beta Carotene; Cell Differentiation; Cell Survival; Epoxy Compounds; Humans; Leukemia, Promyelocytic, Acute; Tretinoin; Tumor Cells, Cultured

(all-E)-beta-Apo- 12'-carotenoic acid and a series of the geometrical isomers were synthesized and their biological activities to inhibit growth and to induce differentiation of human acute promyelocytic leukemia cell line HL-60 were analyzed. It was found that (all-E)-beta-apo- 12'-carotenoic acid (I, Fig. 1) and (15' -Z)-apo- 12'-carotenoic acid (II, Fig. 1) showed strong activity both in inhibition of growth and the induction of differentiation. The biological activity of (13'-Z)-beta-apo- 12'-carotenoic acid (III, Fig. 1) was modest, while that of (13', 15'-di-Z)-beta-apo- 12'-carotenoic acid (IV, Fig. 1) was negligible. (all-E)-beta-Apo- 12'-carotenoic acid and the geometrical isomers acted additively with (all-E)-retinoic acid, and synergetically with (9-Z)-retinoic acid. In accord with our previous report, biological activities of (all-E)-beta-apo- 14'-carotenoic acid (V, Fig. 1) and of (15-Z)-beta-apo- 14'-carotenoic acid (VI, Fig. 1) were very weak. It was indicated that (all-E)-beta-apo- 12'-carotenoic acid, an intermediate metabolite of excentric cleavage pathway of beta-carotene, per se may exert the biological function.

Topics: beta Carotene; Carotenoids; Cell Differentiation; Cell Division; Drug Synergism; Humans; Leukemia, Promyelocytic, Acute; Molecular Structure; Tretinoin; Tumor Cells, Cultured