Induction of differentiation of human promyelocytic leukemia cell line HL-60 by retinoyl glucuronide, a biologically active metabolite of vitamin A.

Abstract

We examined the differentiation activity of retinoyl p-D-glucuronide, a biologically active physiological metabolite of vitamin A, using the human promyelocytic leukemic cell line HL-60, which can be induced to differentiate with retinoic acid. Retinoyl /3-D-glucuronide (1 ,AM) inhibited HL-60 cell proliferation by 55-75%, inhibited tritiated thymidine incorporation into DNA by 63-80%, and induced 38-50% of the cells to differentiate into mature granulocytes. The potency of growth inhibition and induction of differentiation by retinoyl .8-D-glucuronide was similar to that of all-trans-retinoic acid. The continuous presence of either retinoyl .l-Dglucuronide or all-trans-retinoic acid was not required to obtain maximum growth arrest and differentiation: a 1-hr exposure of HL-60 cells to the retinoids gave the same response (measured after a total incubation time of 48 hr) as a 24-hr or 48-hr continuous treatment. Retinoyl j3-D-glucuronide (0.1-0.2 mM) was 50% less cytotoxic to HL-60 cells than all-trans-retinoic acid at an equimolar concentration. Retinoyl P-D-glucuronide was not significantly metabolized to other retinoids; retinoic acid was not formed during incubation. We conclude that retinoyl ,8-D-glucuronide can arrest HL-60 cell proliferation and induce their differentiation into mature granulocytes; it may act by itself or by being hydrolyzed to retinoic acid, which could be immediately utilized and metabolized. The therapeutic use of this retinoid as an antineoplastic agent is suggested.

Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids

“…Acute myeloid leukemia occurs as a result of the propagation of cell clones that have a block in their differentiation pathway to functional mature granulocytes or monocytes ( 120 ). The human cell line HL-60 was developed ( 121 ) and has been widely used to examine the compounds that induce maturation of these cells.…”

Fetal calf serum and retinoic acid affect proliferation and terminal differentiation of a rat rhabdomyosarcoma cell line (BA-HAN-1C)

“…We did not succeed, however, in converting all the cells of BA-HAN-IC into terminally differentiated post-mitotic myotube-like giant cells after exposure to retinoic acid. In our clonal cell line BA-HAN-1C, the coexistence of diverse subpopulations is not very likely to account for this partial refractoriness to retinoic acid as was suggested for other tumour models (Sherman et al, 1986;Zile et al, 1987 (Jetten, 1980;Craig et al, 1984;Amatruda et al, 1985;Thiele et al, 1985;Bentley & Groudine, 1986). Therefore, our clonal cell line should provide a useful system for further investigations concerning the interrelations between polypeptide growth factors and retinoic acid, both of which affect the proliferation and differentiation of tumour cells.…”

Vitamin A derivatives in the prevention and treatment of human cancer.

“…Recent work has also discovered certain metabolites of vitamin A, which are as active as vitamin A in vitro, but unlike vitamin A, are water-soluble and less toxic [15]. Further investigation along these lines will lead to a better understanding of retinoids' mechanism of action and may lead to important clinical advances.…”

“…In addition to the synthetic vitamin A analogues, interest is growing in newly synthesized compounds which are structurally distinct from retinoids and arotinoids but possess potent retinoidlike activity in vitro [13][14][15]. Recent work has also discovered certain metabolites of vitamin A, which are as active as vitamin A in vitro, but unlike vitamin A, are water-soluble and less toxic [15].…”

“…Analysis of the structure-function relationships of retinoids (natural, synthetic, and metabolites) and new retinoid-like compounds should help our understanding of the mechanism of retinoid action and provide direction to future clinical study [13][14][15]. Illustating the marked specificity of different synthetic analogs is the example of 4HPR, which has a high therapeutic index in rat mammary tumor models but not in rodent skin models [4].…”