9-cis-retinoic acid: effects on normal and leukemic hematopoiesis in vitro

Abstract

Retinoic acid exhibits effects on the proliferation and differentiation of many hematopoietic cells. Cellular responsiveness to retinoic acid (RA) is conferred through two distinct classes of nuclear receptors, the RA receptors (RARs) and the retinoid X receptors (RXRs). The RARs bind to both 9-cis- and all-trans-RAs, but 9-cis-RA alone directly binds and activates RXR. This suggested that 9-cis-RA could have expanded hematopoietic activities as compared with all-trans-RA. We compared the abilities of 9-cis- and all-trans-RAs to induce differentiation and inhibit proliferation of three acute myelogenous leukemia (AML) cell lines and fresh leukemic cells from 28 patients and found that: (1) 9-cis-RA in general was more potent than all-trans-RA in suppressing the clonal growth of two AML cell lines and 17 AML samples from patients, including four from individuals with acute promyelocytic leukemia (APL). Eleven leukemic samples, including three from patients with chronic myelogenous or chronic myelomonocytic leukemia, were relatively refractory to both retinoids. (2) The range of activities of both retinoids was similar except that the clonal growth of samples from three AML patients were inhibited by 9-cis-RA, but not by all-trans-RA. (3) Both retinoids inhibited the clonal proliferation of leukemia cells without necessarily inducing their differentiation; in fact, the only fresh AML cells that were able to undergo differentiation were from patients with APL and one individual with M2 AML. (4) Both retinoids enhanced myeloid and erythroid clonal growth from normal individuals, and 9-cis-RA showed slightly more stimulation of the myeloid clonal growth than did the all-trans-RA. Our study suggests that 9-cis-RA is worthy of further study for the treatment of selected individuals with AML.

Peroxisome proliferator‐activated receptor γ ligands stimulate myeloid differentiation and lipogenensis in human leukemia NB4 cells

“…However, this therapy has one problem, that is, the prolonged use of a high dose of ATRA provoked expression of cytosolic retinoic acidbinding proteins, which resulted in the leukemic cells becoming resistant to the induction of differentiation (Cornic et al 1992). 9-cis-Retinoic acid (9-cis RA), an isomer of ATRA that can bind both RAR and RXR, also proved to be potent in inducing differentiation Sakashita et al 1993). In addition, Evans et al reported that the combination of a PPARγ ligand and an RXRα ligand induced monocytic differentiation of some myeloid leukemia cell lines (HL-60 and THP-1) Tontonoz et al 1998).…”

Superior effect of 9‐cis retinoic acid (RA) compared with all‐trans RA and 13‐cis RA on the inhibition of clonogenic cellgrowth and the induction of apoptosis in OCI/AML‐2 subclones: is the p53 pathway involved?

“…The results are mean values of two experiments. Koeffler, 1982b;Wang et al, 1989;Koistinen et al, 1991;Tohda et al, 1992;Sakashita et al, 1993). Their apoptosisinducing effect on AML cells is also well-known (Park et al, 1994;Nagy et al, 1995;Bruel et al, 1997;Zheng et al, 1997).…”

“…All-trans retinoic acid (ATRA), 9-cis RA and 13-cis RA are retinoids involved in normal and malignant haematopoiesis (Douer & Koeffler, 1982a;Bradley et al, 1983;Januszewicz & Cooper, 1984;Nilsson et al, 1984;Gratas et al, 1993;Sakashita et al, 1993;Tsai & Collins, 1993;Van Bockstaele et al, 1993). They are able to induce differentiation of acute promyelocytic leukaemia (APL) cells (Breitman et al, 1980(Breitman et al, , 1981Lawrence et al, 1987;Chomienne et al, 1990;Chen et al, 1991) and are now used, particularly ATRA, in the first-line treatment of APL, a subtype of acute myeloblastic leukaemia (AML) (Huang et al, 1988;Castaigne et al, 1990;Chen et al, 1991;Fenaux et al, 1993).…”

“…They are able to induce differentiation of acute promyelocytic leukaemia (APL) cells (Breitman et al, 1980(Breitman et al, , 1981Lawrence et al, 1987;Chomienne et al, 1990;Chen et al, 1991) and are now used, particularly ATRA, in the first-line treatment of APL, a subtype of acute myeloblastic leukaemia (AML) (Huang et al, 1988;Castaigne et al, 1990;Chen et al, 1991;Fenaux et al, 1993). In the other AML subtypes, retinoids have also been found to be effective in inhibiting AML cell growth (Douer & Koeffler, 1982b;Wang et al, 1989;Koistinen et al, 1991;Tohda et al, 1992;Sakashita et al, 1993) and inducing apoptosis in vitro (Zheng et al, 1997). ATRA-induced apoptosis has been studied in more detail and was found to be associated with the downregulation of bcl-2 (Delia et al, 1995;Bradbury et al, 1996;Pisani et al, 1997;Hu et al, 1998).…”

“…There are only a few studies that have compared the effects of different retinoids on AML cells. In one study, it was found that the effects of 9-cis RA were more prominent than other retinoids on AML cells in vitro (Sakashita et al, 1993).…”