This might be due to their lower affinity for CRABP compared with ATRA, which has progressive reduction of plasma levels with continuous treatment.
In vitro all-trans retinoic acid (ATRA) sensitivity and cellular retinoic acid binding protein (CRABP) levels in relapse leukemic cells after remission induction by ATRA in acute promyelocytic leukemia.
After in vitro and clinical experiences with ATRA over a decade, the following mechanisms involved in development of the drug resistance have been proposed (Figure 4): 1) induction of accelerated metabolism of ATRA; 2) increased expression of cellular retinoic acid binding proteins (CRABPs); 3) constitutive degradation of PML-RAR[alpha]; 4) point mutations in the LBD of RAR[alpha] of PML-RAR[alpha]; 5) P-glycoprotein expression; 6) transcriptional repression by HDAC activity; 7) isoforms of PML-RAR[alpha]; 8) persistent telomerase activity; 9) expression of type II transglutaminase; and 10) topoisomerase II activity.
First, the model cannot be cyclic; hence, increases in CRABP
as a function of RARB that might then result in greater binding of RA in the cytosol, reducing RARB expression, could not be included.
These results represent the first report of CRABP expression during adipocyte differentiation of bovine intramuscular fibroblast-like cells by RA and it appears that CRABPs are differentially expressed during adipogenesis and modulated by RA concentrations.
Molecular cloning of two human cellular retinoic acid-binding proteins (CRABP).
These results suggest that CRABPs may play an important role in the regulation of intracellular retinoic acid concentrations during adipogenesis.