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.

Induced Differentiation of Human Myeloid Leukemia Cells into M2 Macrophages by Combined Treatment with Retinoic Acid and 1α,25-Dihydroxyvitamin D3

“…9cRA (100 nM) increased NBT-reducing activity in THP-1 and HL60 cells, while ATRA (100 nM) was not effective ( Fig. 1A ), consistent with the previous reports showing that 9cRA is more potent than ATRA in inducing differentiation of leukemia cells [20] , [31] , [32] . In combination with 1,25(OH) 2 D 3 , 9cRA and ATRA effectively increased NBT-reducing activity in these cells ( Fig.…”

“…9cRA exhibits differentiation-inducing activity more effectively than ATRA in the absence or presence of 1,25(OH) 2 D 3 ( Figs. 1 and 2 ), in agreement with previous reports [20] , [31] , [32] . Since 9cRA acts as a ligand for both RAR and RXR [40] , synergistic activation may be due to binding to both RAR and RXR in the RAR−RXR heterodimer.…”

Traffic lights for retinoids in oncology: molecular markers of retinoid resistance and sensitivity and their use in the management of cancer differentiation therapy

“…Retinoids have critical functions in many aspects of human biology: at the cellular level, they control cell differentiation, growth, and apoptosis [ 3 ]. Several biologically active vitamin A derivatives, namely, all- trans retinoic acid (ATRA), 9- cis retinoic acid (9- cis- RA), and 13- cis retinoic acid (13- cis -RA), have been tested for potential use in cancer therapy and chemoprevention [ 4 – 7 ]. The most effective clinical use of ATRA was demonstrated in acute promyelocytic leukemia (APL) treatment [ 8 ].…”

Reprogramming acute myeloid leukemia into sensitivity for retinoic-acid-driven differentiation

“…Several studies have explored the efficiency of ATRA and liposomal ATRA in combination with chemotherapy to induce differentiation and apoptosis or to reduce clonogenic capacity in non-APL AML cell lines [86,87] and primary AML patient cells [88][89][90]. Moreover, some clinical trials showed the effectiveness of ATRA in combination with chemotherapy for AML patients [91,92], whereas others had disappointing results [93][94][95][96].…”