Partial restoration of all trans retinoic acid (ATRA) sensitivity by compactin in ATRA-resistant leukemic cells (ATRA-R HL-60).
The resistance to all trans retinoic acid (ATRA) differentiating treatment is a consequence, in most of the cases, of either increased catabolism or down regulation of ATRA uptake. Recently, we have shown that ATRA efficiency to differentiate HL-60 cells was enhanced about 30 times after its incorporation into Low Density Lipoprotein (ATRA-LDL). Here, we attempted to differentiate the ATRA-resistant HL-60 cells by ATRA-LDL at high concentrations up to 10 microM. No significant differentiating effect was observed, although the LDL receptor sites were evidenced in these cells. To increase the number of LDL receptors, the cells were pre-incubated in lipoprotein-deprived serum medium and compactin (2 microM), both ATRA and ATRA-LDL induced gradual increase of cell differentiation (35%+/-1 and 51.5%+/-5 at 10 microM of ATRA and ATRA-LDL respectively). At 2 and 8 microM, the intracellular concentrations of ATRA were respectively three and four times higher when incorporated into LDL. In addition, ATRA-LDL, in the medium, was better protected against degradation than ATRA. The surprising restoration of free ATRA sensitivity after treatment with compactin suggested the implication of new mechanisms unrelated to the LDL-receptor endocytosis but involving the non-sterol pathway.
Gueddari
N
N
EA2063 TFR53 Biomolécules Laboratoire de Biochimie, U.F.R. de Pharmacie 51 rue Cognacq-Jay 51096, Reims, France.
Madoulet
C
C
Lefebvre
P
P
Berthou
L
L
Chomienne
C
C
Jardillier
J C
JC
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011973:Receptors, LDL / Q000378:metabolism; D014212:Tretinoin / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011973:Receptors, LDL; C012258:mevastatin; D014212:Tretinoin; D008148:Lovastatin