Mutation in the ligand-binding domain of the retinoic acid receptor alpha in HL-60 leukemic cells resistant to retinoic acid and with increased sensitivity to vitamin D3 analogs.
Even though retinoic acid can induce complete remissions in patients with acute promyelocytic leukemia, the duration of response is short and further therapy with this agent is less effective, suggesting the development of drug resistance. One possible way to overcome this problem is to use retinoic acid in combination with another agent that can induce differentiation, such as vitamin D3 or its analogs. In order to understand the mechanism of drug resistance to retinoic acid, we have isolated a clone of human HL-60 myeloid leukemic cells that is resistant to all-trans retinoic acid by continuous exposure to this agent. We have observed that the resistant cell line was also resistant to 9-cis-retinoic acid and more sensitive to the antileukemic action of the vitamin D3 analog, 1,25-dihydroxy-16-ene- 23-yne-26,27-F6-cholecalciferol. In addition, this combination showed synergistic antileukemic action against the wild type HL-60 leukemic cells. DNA sequence analysis revealed a mutation in the ligand binding region of retinoic acid receptor alpha in the HL-60/RA cells in which a glycine was replaced by an aspartic acid. Using gel retardation assays, we observed a large reduction in the formation of RXR-RAR heterodimers in the HL-60/RA cell line as compared to the parental cell line. This mutation in the retinoic acid receptor alpha of the HL-60/RA cells may be responsible for drug resistance to ATRA and 9-cis-retinoic acid and increased sensitivity to vitamin D3 analogs.
Doré
B T
BT
Départment de pharmacologie, Université de Montréal, Québec, Canada.
Momparler
R L
RL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D018922:HL-60 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D002117:Calcitriol